KR20200052298A - Targeted drugs related to trimethylamine and / or trimethylamine N-oxide - Google Patents

Abstract

Embodiments of the methods and / or systems include CutC enzymes and / or CntA enzymes associated with microorganisms from at least one taxonomic group from a set of microbial taxonomic groups in a patient having one or more conditions associated with at least one of TMA, TMAO and / or derivatives thereof. Administering a therapeutically effective amount of a compound that affects inhibition of one or more of the above.

Description

Targeted drugs related to trimethylamine and / or trimethylamine N-oxide

This application claims the priority of U.S. Provisional Application No. 62 / 545,056 filed on August 14, 2017, which is incorporated herein by reference. This application also claims the priority of U.S. Provisional Application No. 62 / 545,065, filed on August 14, 2017, which is incorporated herein by reference.

The present invention generally relates to microbiology.

The concept of drugging a microbial target (eg, drug injection into a microbiome) does not directly target human cells and / or avoid side effects resulting from gene therapy; And one or more therapeutic approaches targeting receptors and enzymes belonging to the microbiota instead. This approach avoids knocking-down of human enzymatic action by gene therapy methods, where these enzymes not only engage in the production of undesirable metabolites, but may also have a beneficial effect on the organism.

Choline is an important nutrient for humans and other organisms and contributes to different roles in biological pathways such as cell membrane function, methyl metastasis events and neurotransmission. In addition to choline, trimethylamine (TMA) metabolites are an important source of nitrogen and also the carbon source of bacteria that convert TMA from greenhouse gas methane in the marine environment. These small molecules are linked through choline trimethylamine-lyase (CutC) enzyme, which is a glycine radical enzyme that produces a trimethylamine (TMA) and acetaldehyde by cutting the CN bond in choline as follows: Is: Choline = trimethylamine + acetaldehyde.

Intestinal bacteria and / or other suitable microorganisms from any suitable body part may play an important role in the initiation and progression of some diseases. The human gut microbiota is described as producing TMA from choline; This is a process found only in microorganisms. Choline degradation is a major source of TMA formation in the intestine. Specifically, intestinal bacterial diet can affect the production of trimethylamine-N-oxide (TMAO), a product of TMA and its derivatives. For example, TMA metabolites, often obtained in meat, eggs (e.g., egg yolk, etc.), fat-rich foods, and / or dairy products, are found in the liver by the action of human flavin-containing monooxygenase 3 (FMO3) enzymes. It is absorbed and converted into TMAO.

Patients with high TMA levels are more likely to have a heart attack. This aspect becomes particularly significant when recent studies have discarded that saturated fat and cholesterol correlate with an increased risk of heart disease and atherosclerosis.

TMAO is a metabolite associated with a high risk of cardiovascular and kidney disease, and high levels of TMAO produced from choline can cause atherosclerosis in mice. Two major TMA synthesis pathways are described in bacteria, one using choline as the substrate (CutC / CutD complex) and the other L-carnitine (two-component Rieske-type oxygenase) Aze / reductase CntA / B) is used. Gene encoding a CntA / B was also described as well as some taxa from several pireu ku test (Firmicute s) belonging to the beta-proteobacteria.

In relation to one of the major TMA synthetic pathways described, this pathway uses choline as the substrate (CutC / CutD complex). TMA is absorbed and converted into TMAO by the action of the FMO3 enzyme in the liver. FMO3 participates in host-gut microbiota metabolic interactions. Some strategies have proposed knocking down expression of FMO3 enzymes using antisense oligonucleotides that inhibit mRNA transcription. Decreasing choline or L-carnitine intake directly can produce undesirable effects, while these molecules can be beneficial even in small amounts, such that the accumulation of TMA (e.g., through the inhibition of FMO3 enzymes) It is also undesirable to inhibit the FMO3 enzyme to reduce TMAO levels, as it produces conditions or side effects such as hepatitis and / or trimethylamineuria (e.g., fish odor syndrome, fish malodor disorder, etc.) It may not.

Decreasing choline or L-carnitine intake directly can produce undesirable effects, while these molecules can be beneficial even in small amounts, such that the accumulation of TMA (e.g., through the inhibition of FMO3 enzymes) It is also undesirable to inhibit the FMO3 enzyme to reduce TMAO levels, as it produces conditions or side effects such as hepatitis and / or trimethylamineuria (e.g., fish odor syndrome, fish malodor disorder, etc.) It may not.

Embodiments of the methods and / or systems include CutC enzymes and / or CutC enzymes associated with microorganisms from at least one taxonomic group from a set of microbial taxonomic groups in a patient having one or more conditions associated with one or more TMAs, TMAOs and / or derivatives thereof. Or administering a therapeutically effective amount of a compound that affects the inhibition of one or more of the CntA enzymes.

In one example, method 100 can overcome side effects and / or complications associated with FMO3 enzyme inhibition by selectively inhibiting TMA production pathways, such as, for example, CutC / CutD and / or CntA / CntB.

1 includes a flowchart representation of a variation of an implementation of the method;
2 includes a flowchart representation of a variation of an implementation of the method;
3 includes a graphical representation of a variation of an implementation of the method.

The following description of implementations is not intended to limit the implementations, but is intended to enable those skilled in the art to make and use them.

1. Outline

1 to 3, an embodiment of the method 100 (eg, to treat a patient with a condition associated with at least one of TMA, TMAO and / or derivatives thereof; etc.) may include one or more A set of microbial taxonomic groups (e.g., drugs, etc.) for a patient having a condition (e.g., one or more conditions associated with at least one of TMA, TMAO and / or derivatives thereof, etc.) One or more targets associated with microorganisms from at least one taxonomic group from Firmicutes (moon) and Proteobacteria (moon) (e.g. CutC enzymes; Liske-type ( Rieske-type) Oxygenase (CntA) enzymes; other enzymes; proteins; other biological targets; non-biological targets; enzymes associated with at least one of TMA, TMAO and / or derivatives thereof; etc. Etc ) May include S110.

In one example, the method 100 (eg, for treating a patient having one or more conditions associated with at least one of TMA, TMAO and / or derivatives thereof, etc.) is applied to a patient having one or more conditions, Pirmiku Administering a therapeutically effective amount of a compound to inhibit the CutC enzyme of a microorganism from at least one of Firmicutes (moon) and Proteobacteria (moon), wherein the compound (eg For example, including one or more components, such as any suitable combination of components, etc.) includes at least one of the following: 2-ethyl-1-butanol; (2R) -3,3-dimethyl-1,2-butanediol; (2S) -3,3-dimethyl-1,2-butanediol; (2S) -4-methyl-2-pentanol; (2S) -3-methyl-2-butanol; (2R) -4-methyl-2-pentanol; (2R) -3-methyl-2-butanol; (2S) -2-pentanol; (2S) -2-methyl-1,4-butanediol; 2-methyl-2,4-butanediol; Trimethylolpropane; 3- (4-methoxyphenyl) propanal; 1- (3-pyridinyl) -2-propanamine; 2-[(2R) -2-butanyl] phenol; 4-propylbenzoic acid; (2S) -1- (benzyloxy) -2-propanol; Methyl 3- (4-hydroxyphenyl) propanoate; α-methylphenylalanine; 2,2-dimethyl-1-phenyl-1-propanol; Methyl (2R) -hydroxy (phenyl) acetate; (2S) -2-phenylpyrrolidinium; 4-methyl-3-phenyl-1,2-oxazole-5-amine; 4,4'-biphenyldiamine;4'-methyl-2-biphenylcarbonitrile;4-biphenylol; 2- [3- (4-methylphenyl) -1,2-oxazol-5-yl] ethanol; 4-biphenylcarboxamide; 4-ethynylbiphenyl; 5- (4-methylphenyl) -1H-1,2,4-triazole-3-amine; 5- (4-methylphenyl) -1H-pyrazol-3-amine; 4-hydroxycatechol; 3-phenyl-1H-pyrazole-5-carbohydrazide; 4-methyl-1,3-benzenediol; N- (2-hydroxyethyl) -1,3-propanediaminium; 3-methoxy-3-methylbutanol; 4-pyridinylmethaneaminium; N-methyl-3-pyridinamine; 2-methoxypyridine; 5-methyl-3-pyridinamine; 1- (4-methyl-3-pyridinyl) methanamine; Mesitylene; (E) -benzaldoxime '(3R) -2,2,4-trimethyl-1,3-pentanediol; (1R, 4R) -2-azabicyclo [2.2.1] hept-2-ylacetic acid; 3-acetylphenol; 3-hydroxybenzoic acid; 1H-indole-7-ylmethanol; 3-vinyl aniline; (3s, 5s, 7s) -1-isocyanatoadamantine (isocyanatoadamantane); (1R, 2S, 5R) -2-hydroxy-2,6,6-trimethylbicyclo [3.1.1] heptan-3-one; (-)-β-pinene; 2H-isoindole-1,3-diamine; (3s, 5s, 7s) -1-adamantanol; (3-aminobicyclo [2.2.1] hep-2-yl) methanol; 3- (hydrazinomethyl) phenol; (1S, 2R) -2-carbamoylcyclohexaneaminium; (1S, 4R) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; (1R, 4S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; Methyl 4-methyl-4-piperidinecarboxylate; Methyl heptanoate; 3-methylpyridazine; 4,5-dimethyl-1,2-oxazol-3-amine; 2- (2-hydroxyethoxy) phenol; 2-hydroxy-N- (3-pyridinylmethyl) ethanaminium; 3-phenyl-1-propanol; (2R) -6-methyl-2-heptanol; 2-phenoxyacetohydrazide; N-hydroxyoctanamide; Cyclobutanecarbohydrazide; Phenylhydrazine; (1S, 4R) -2-azabicyclo [2.2.1] hep-5-en-3-one; Salicylamide; Adamantane; 3-azabicyclo [3.3.1] nonane; N-hydroxy-2-methylbenzenecarboximideamide; (-)-Campen; (1S, 2S, 4S) -bicyclo [2.2.1] hept-5-en-2-ylmethanol; Dicyclopentadiene; (8-anti) (anti) -3-azabicyclo [3.2.1] octane-8-ol; (1R, 2S, 6R, 7S) -tricyclo [5.2.1.02,6] deca-3,8-diene; Any suitable compound, including any suitable combination of any suitable compound and / or structure (eg, one or more structures, etc.) included in Tables 1-4; And / or pharmaceutically acceptable forms and / or salts thereof.

In one example, the method 100 (eg, for treating a patient having one or more conditions associated with at least one of TMA, TMAO and / or derivatives thereof, etc.) is applied to a patient having one or more conditions, Pirmiku Administering a therapeutically effective amount of a compound for inhibiting the CntA enzyme of a microorganism from at least one of Firmicutes (moon) and Proteobacteria (moon), wherein the compound (eg For example, including one or more components, such as any suitable combination of components, etc.) includes at least one of the following: N-methylglutamic acid; 4- (1-pyrrolidinyl) butanoic acid; 4-methyl-4-piperidinecarboxylic acid; Isonifecotic acid; N-propylbenzene; N-ethyl-2-pyridinamine; (4R) -4-amino-1-propyl-2-pyrrolidinone; 2,5-diaminotoluene; Ethyl phenyl ether; Phenyl cyanate; 1- (2-cyclopenten-1-yl) acetone; 2-amino-3-methylpyridinium; E-pyridine-3-aldoxime; N-cyclohexyl formamide; 2-methyl-2-hexenic acid (hexenoic acid); 4-heptanaminium; 3,4-anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid; 2,2 '-[(2-hydroxyethyl) imino] diacetic acid; 1H-tetrazol-5-ylacetic acid; Diacetylacetone; (2S) -2-acetoxy propanoic acid; 4,4'-biphthalic anhydride; Bis (1H-benzotriazol-1-yl) methanone; 2-anthraquinone sulfonic acid; 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzonitrile .; 2-phenylquinazolin-4-ol; 4-amino-2- (1,3-benzothiazol-2-yl) phenol; 4-phenyl-1 (2H) -phthalazinone; 5- (1,3-benzodioxol-5-yl) -2-methyl-3-furo acid; (5R) -5- (2-naphthyl) dihydro-2 (3H) -furanone; 3- [5- (3-methylphenyl) -1,3,4-oxadiazol-2-yl] propanoic acid; 9-ethynylphenanthrene; PHA-767491; 3-amino-2-methylphenol; 5- (4-methylphenyl) -2-furo acid; 8-methyl-4H-thieno [3,2-c] chromen-2-carboxylic acid; Resorcinol monobenzoate; 3-methoxy-4-biphenylcarbaldehyde; (7-amino-4-methyl-2-oxo-2H-chromen-3-yl) acetic acid; 2,3-dihydro-1H-inden-5-yl (oxo) acetic acid; 3- (2-pyridyl) aniline; 4- (3-methyl-1H-1,2,4-triazol-5-yl) aniline; Benzidine; (DL) -3-O-methyldopa; Methyl (2E) -3- (2-amino-5-methyl-3-pyridinyl) acrylate; (5-methylfuro [2,3-b] pyridin-2-yl) methanol; (2R) -2,3-dihydro-1,4-benzodioxin-2-ylmethaneaminium; R-phenylethyl propionate; i-propyl benzoate; 4-acetotoluide; (1S) -1- (2,5-dimethylphenyl) ethanaminium; (1R) -2-methyl-2,5-cyclohexadiene-1-carboxylic acid; (2,2-dimethoxyethyl) benzene; Any suitable compound, including any suitable combination of any suitable compound and / or structure (eg, one or more structures, etc.) included in Tables 5-8; And pharmaceutically acceptable forms and / or salts thereof.

Additionally or alternatively, as shown in FIGS. 2-3, an embodiment of the method 100 (eg, for treating a patient having a condition associated with at least one of TMA, TMAO and / or derivatives thereof) To identify at least one compound; etc.) may be selected from one or more targets (e.g., CutC enzymes; CntA enzymes; other enzymes; proteins; other biological targets; non-biological targets; TMA, TMAO and / or derivatives thereof) Determining one or more representative sequences (e.g., nucleic acid sequences; amino acid sequences, etc.) of at least one enzyme associated with it; It represents one or more sequences of one or more target set for the taxon (e.g., pireu ku test (Firmicutes) (gate) and the proteosome, such as a minute different from bacteria (Proteobacteria), (Q) Representative representing the plurality of the sequence of the target from the plurality of group sequences); Generating one or more models of one or more targets (eg, protein structural models, etc.) based on one or more representative sequences of one or more targets; One or more experiments with one or more models and one or more control molecules (e.g., 3,3-dimethyl-1-butanol; L-carnitine, etc.) (e.g., control docking simulations; other computational simulations; other Determining one or more control binding parameters (and / or other suitable interaction parameters, etc.) for the one or more targets based on experiments, etc.); Experimental set (e.g., control docking simulation) using one or more models and a library of compounds (e.g., likely to affect one or more targets, such as the possibility to inhibit the CutC enzyme and / or CntA enzyme) Determining a set of compound binding parameters (and / or other suitable interaction parameters, etc.) for one or more targets based on different computer simulations; other experiments, etc.); Based on a comparison between one or more control binding parameters (and / or other suitable interaction parameters related to one or more control molecules, etc.) and a set of compound binding parameters (and / or other suitable interaction parameters related to a compound, etc.), TMA , Identifying at least one compound (eg, from a library of compounds, etc.) for treating a patient having a condition associated with one or more of TMAO and derivatives thereof S160; And / or verifying at least one compound at step S170.

Implementations of method 100 and / or system 200 may include, for example, at least one associated with one or more conditions (eg, correlated with, causing, etc.) and / or from a set of taxa. Affecting one or more targets associated with microorganisms from the taxonomic group (from at least one of Firmicutes (moon) and Proteobacteria (moon), etc.) (e.g., CutC enzyme inhibition; CntA enzyme Inhibition, etc.) Diagnosing one or more patients with one or more conditions associated with at least one of TMA, TMAO and / or derivatives thereof by use and / or administration (and / or other suitable supply and / or promotion) of one or more compounds. And / or a function of treatment. Additionally or alternatively, embodiments of method 100 and / or system 200 may include one or more conditions (eg, associated with at least one of TMA, TMAO, and / or derivatives thereof, etc.). May serve to identify one or more compounds that may be administered to treat the patient.

In one example, the method 100 is based on a molecular docking simulation, for example, a therapeutic effect on a condition associated with TMA, TMAO and / or derivatives thereof (eg, TMA; TMAO; derivatives thereof, etc.) To identify compounds with inhibition (by inhibiting production), from microorganisms (e.g., from Firmicutes (moon) and / or Proteobacteria (moon), etc.), and from TMA, TMAO and And / or a library of compounds can be screened to identify compounds associated with TMA, TMAO and / or derivatives thereof that can bind to the active site of one or more targets associated with their derivatives. In one example, method 100 can overcome side effects and / or complications associated with FMO3 enzyme inhibition by selectively inhibiting TMA production pathways, such as, for example, CutC / CutD and / or CntA / CntB.

The condition (e.g., which can be treated with one or more compounds) is preferably characterized and / or therapy for one or more microbial-related conditions associated with at least one of TMA, TMAO and / or derivatives thereof (therapies) related conditions (e.g., may be caused by one or more of TMA, TMAO and / or derivatives thereof, such as large amounts of TMA, TMAO and / or derivatives thereof) Condition, and / or related in other ways). The condition associated with at least one of the TMA, TMAO and / or derivatives of the two may include any one or more of the following: cardiovascular conditions (eg, atherosclerosis; severe heart failure; coronary heart disease; inflammatory heart disease) ; Valve heart disease; obesity; stroke; thrombosis, platelet reactivity, etc.); Kidney disease (eg, kidney failure; chronic kidney disease; polycystic kidney disease; glomerulonephritis; IgA nephropathy; nephritis; kidney syndrome; lupus; kidney cancer; rare kidney disease; etc.); Metabolic conditions (eg, trimethylamineuria (TMAU), etc.); Nutrition-related conditions (e.g., weight-related conditions such as weight-loss conditions; blood sugar-related conditions such as hyperglycemia-related conditions; allergies related to wheat, gluten, dairy, soybeans, peanuts, shellfish, nuts, eggs, etc.) And / or an allergic-related condition such as intolerance.

Additionally or alternatively, the condition can include any one or more of the following: gastrointestinal-related conditions (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Seceliac disease, Crohn's disease, blotting (bloating), hemorrhoids disease, constipation, reflux, bloody stools, diarrhea, etc.); Skin-related conditions (e.g. acne, dermatitis, eczema, rosacea, dry skin, psoriasis, dandruff, photosensitivity, rough skin, itching, flaking, scaling, peeling) , Fine lines or cracks, gray skin of dark-skinned individuals, redness, deep cracks such as cracks that can bleed and lead to infection, itching and scaling of the skin of the scalp, irritated Oily skin such as oily skin, skin sensitivity to products such as hair care products, scalp microbiome imbalance, etc.); Exercise-related conditions (eg, gout, rheumatoid arthritis, osteoarthritis, reactive arthritis, multiple sclerosis, Parkinson's disease, etc.); Cancer-related conditions (e.g., lymphoma; leukemia; blastoma; germ cell tumor; carcinoma; sarcoma; breast cancer; prostate cancer; basal cell cancer; skin cancer; colon cancer; lung cancer; cancer conditions associated with any suitable physiological region; etc.) ); Anemia condition; Neuro-related conditions (eg, ADHD, ADD, anxiety, Asperger's syndrome, autism, chronic fatigue syndrome, depression, etc.); Autoimmune-related conditions (eg, Sprue, AIDS, Sjogren's, lupus, etc.); Endocrine-related conditions (eg, obesity, Graves' disease, Hashimoto's thyroiditis, metabolic disease, type I diabetes, type II diabetes, etc.); Lyme disease condition; Communication-related conditions; Sleep-related conditions; Pain-related conditions; Genetic-related conditions; Chronic disease and / or other suitable type of condition. Additionally or alternatively, the condition may include one or more of the human behavioral conditions, which may include any one or more of the following: caffeine consumption, alcohol consumption, consumption of other food items, dietary supplement consumption, probios May include one or more human behavioral conditions that may include one or more of tick-related behaviors (e.g. consumption, avoidance, etc.), other dietary behaviors, habitual behaviors (e.g. smoking, low, Athletic conditions, such as moderate and / or excessive athletic conditions), menopause, other biological processes, social behavior, other behavioral and / or other appropriate human behavioral conditions.

The condition may include one or more of the following: disease, symptom, cause (e.g., trigger, etc.), disability, associated risk (e.g., propensity score, etc.), related severity, behavior (e.g. For example, caffeine consumption, habits, diet, etc.), and / or other suitable aspects related to the condition. The condition can be related to any suitable phenotype (eg, a measurable phenotype for humans, animals, plants, fungi, etc.).

In examples, the condition (eg, one or more conditions, etc.) may include at least one of the following: cardiovascular conditions (eg, atherosclerosis, etc.), kidney conditions (eg, kidney failure, etc.), metabolism -Related conditions (eg, trimethylamineuria, etc.) and / or nutrition-related conditions (eg, weight-related conditions; hyperglycemic-related conditions, etc.); Wherein the condition may be related to at least one of TMA, TMAO and / or derivatives thereof; And wherein the step of administering to one or more patients comprises a therapeutically effective amount of one or more compounds (e.g., including any suitable compound in Tables 1-8 and / or any suitable combination of compounds therefrom; etc.). Of at least one enzyme (eg, CutC enzyme; CntA enzyme; TMA, TMAO and / or derivatives thereof) of a microorganism from at least one of Firmicutes (moon) and / or Proteobacteria (moon) Administration to one or more patients with one or more conditions (eg ;; etc.) to inhibit one or more related enzymes, etc.).

Additionally or alternatively, the data described herein (eg, binding parameters; interaction parameters; identified compounds; outputs from models and / or experiments, etc.) may include any of the following: It may be associated with a suitable temporal indicator (eg, seconds, minutes, hours, days, weeks, periods, time points, time stamps, etc.): data is collected, determined, transmitted, received and / or otherwise A time indicator indicating when processed; A time indicator that provides context to the content described by the data; Changes in time indicators (eg, data over time; changes in data; data patterns; data trends; data extrapolation and / or other predictions, etc.); And / or other suitable indicators related to time.

Additionally or alternatively, parameters, metrics, inputs, outputs, and / or other suitable data can be associated with a value type including any one or more of the following: score (eg For example, binding parameters; interaction parameters, etc., binary values (e.g., presence of targets in a microbial taxonomy, etc.), classification (e.g., taxonomy, etc.), confidence levels, identifiers (e. , Compound identifiers, etc.), spectral values and / or any other suitable type of value. Any suitable type of data described herein (eg, for different models described herein; for some of the method 100 implementations; etc.) can be used as input, and output (eg, a model And) and / or can be manipulated in any suitable manner for any suitable configuration associated with implementations of method 100 and / or system 200.

Some of the one or more instances and / or implementations of the method 100 and / or process described herein may include one or more instances of the implementation, configuration, and / or entity described herein of the system 200. By and / or using it asynchronously (e.g., sequentially), simultaneously (e.g., in parallel; screening and) in a temporal relationship with a trigger event (e.g., performance of a portion of method 100) And / or simultaneous screening in different threads for parallel computing to improve system throughput for compound determination in different ways and / or for compound determination in different ways, etc.) and / or any suitable It can be performed in any other suitable order in time and frequency.

Embodiments of system 200 may include any one or more of the following: compounds and / or pharmaceutically acceptable forms thereof, and / or salts of sons (eg, pharmaceutically acceptable salts) Etc); Computing systems (eg, for identifying one or more compounds, etc.); Sample handling network; Sequencing system; And / or any other suitable component. System 200 and / or portions of system 200 may be executed, hosted, communicated, and / or otherwise included in whole or in part by: a remote computing system (eg, a server, At least one network computing system, stateless, stateful, etc., local computing system, user device (eg, mobile phone device, other mobile device, personal computing device, tablet, wearable, head -Mountable wearable computing device, wrist-mountable wearable computing device, etc.), care provider device, database, application programming interface (API) (e.g., for accessing data described herein) and / or any suitable configuration Element. Communication by and / or between any of the components of the system 200 may include wireless communication (eg, WiFi, Bluetooth, radio frequency, Zigbee, Z-wave, etc.), Wired communication and / or any other suitable type of communication. The components of system 200 may be physically and / or logically in any way (eg, with respect to some of the implementations of method 100, etc., with any suitable distribution of functionality across components) ) Can be integrated.

Some of the implementations of method 100 and / or system 200 may be performed by one or more of the following: first parties; Third parties; Car providers (eg, doctors, nurses, etc.); Laboratory technicians; user; Compound providers; And / or any suitable entities.

However, implementations of method 100 and / or system 200 may be configured in any suitable manner.

2.1 Compound management

Embodiments of method 100 include one or more compounds (e.g., a therapeutically effective amount of one or more compounds, etc.) associated with one or more conditions (e.g., TMA, TMAO and / or at least one derivative thereof) Administration to one or more patients having a condition, etc.) may include S110 (and / or other suitable provision; facilitation, etc.), which may function to facilitate treatment of one or more patients.

A therapeutically effective amount of one or more compounds is preferably administered, but any suitable amount of one or more compounds can be administered.

The compound (e.g., drug; molecule, etc.) preferably has the effect of a condition associated with the derivative of TMA, TMAO and / or their derivatives (e.g., TMA, TMAO, and / or derivatives thereof) Preferably affects one or more targets (e.g., CutC enzymes; CntA enzymes, etc.) associated with at least one of TMA, TMAO and / or derivatives thereof (such as for preventing, treating and / or reducing) For example, suppression, etc.). Additionally or alternatively, the compound may affect one or more targets differently (eg, activation, up-regulation, down-regulation, binding, etc.), and / or the target may be associated with any suitable condition. Can be. The compounds are any suitable combination of compounds included in Tables 1-8 (e.g., one or more; combinations; individual molecules and / or compounds, etc.), their derivatives, their pharmaceutically acceptable forms and / or these It may include any suitable form of.

The compound may include any suitable pharmaceutically acceptable form of the compound, which may include any one or more of the following: derivatives; Pharmaceutically deliverable form; Forms with carriers, agonists, supplements; salts; And / or any suitable acceptable form. The compounds may include any suitable salts thereof (eg, pharmaceutically acceptable salts, etc.) and / or the form of any suitable compound.

Targets (e.g., targets targeted by one or more compounds; targets, such as in relation to one or more conditions, related and / or otherwise associated to induce, contribute to, a therapeutic effect) include any one or more of the following: Can: CutC enzyme; CntA enzyme; CutD enzyme; CntB enzyme; Other enzymes (eg, those associated with at least one of TMA, TMAO and / or derivatives thereof); protein; Target markers (eg, biomarkers, etc.); Target of interest; Known or identified targets; Unknown or previously unknown targets; Gene targets; Sequences (eg, amino acid sequences; nucleic acid sequences, etc.); compound; Peptides; carbohydrate; Lipids; Nucleic acids; Cells (eg, whole cells, etc.); Metabolites; Natural products; Diagnostic biomarkers; Prognostic biomarkers; Predictive biomarkers; Other molecular biomarkers; Biological targets; Non-biological targets; Other molecules (eg, those associated with at least one of TMA, TMAO and / or derivatives thereof); And / or any other suitable target.

The target is preferably associated with a microorganism from at least one taxonomic group from a set of microbial taxonomic groups (e.g., from at least one of Firmicutes (moon) and Proteobacteria (moon)). (E.g., derived from a microorganism; produced by a microorganism; found in relation to a microorganism; present in a microorganism; encoded by the microorganism's genetic sequence, amino acid sequence and / or other suitable sequence). Additionally or alternatively, targets can be microbial and / or visceral, skin, nose, mouth, and genitals from any suitable microbial taxonomy (e.g., domain, family, door, river, neck, family, genus, species, etc.). And / or microorganisms associated with any suitable body part, including one or more of any suitable body part. Administering the compound can include any one or more of providing, promoting and / or otherwise administering the compound.

Administering one or more compounds inhibits CutC enzymes, such as the cutC enzyme of a demon from at least one of Firmicutes (moon), Proteobacteria (moon) and / or other suitable taxonomic groups (and And / or administering (eg, a therapeutically effective amount; etc.) one or more compounds (to otherwise affect).

A compound that inhibits (and / or otherwise affects) a CutC enzyme (eg, associated with a microorganism from at least one of Firmicutes and Proteobacteria ) is one or more 3,3-dimethyl -1-butanol (DMB) analogs (e.g., with the same or higher affinity for the CutC enzyme than DMB, as in the case of CutC enzymes belonging to Firmicutes and / or Proteobacteria ) And the like). In an example, DMB can inhibit TMA formation by the CutC enzyme (eg, from a microorganism cultured in a non-lethal way, such as not an antibiotic); Can reduce TMAO levels (eg, in animals with a high choline or carnitine diet, etc.); And / or to the active site of the CutC enzyme (eg, with a higher affinity than choline, thus inhibiting competition, etc.). In examples, DMB analogs (and / or compounds) may include any one or more compounds included in Table 1.

Proteobacteria ( Proteobacteria ) And / or Pirmicutes ( Firmicutes From  Microbial CutC  Examples of DMB analogs that can bind to enzymes rescue SMILES code IUPAC nomenclature Binding energy (for CutC enzyme, Proteobacteria ) Binding energy (for CutC enzyme, Pirmicutes )

CCC (CC) CO
2-ethyl-1-butanol
-4.9 kcal / mol

CC (C) (C) [C @ H] (CO) O (2R) -3,3-dimethyl-1,2-butanediol -5.5 kcal / mol -5.2 kcal / mol

CC (C) (C) [C @@ H] (CO) O (2S) -3,3-dimethyl-1,2-butanediol -5.4 kcal / mol -5.2 kcal / mol

C [C @@ H] (CC (C) C) O (2S) -4-methyl-2-pentanol -5.2 kcal / mol

C [C @@ H] (C (C) C) O (2S) -3-methyl-2-butanol -4.8 kcal / mol

C [C @ H] (CC (C) C) O (2R) -4-methyl-2-pentanol -5.0 kcal / mol

C [C @ H] (C (C) C) O (2R) -3-methyl-2-butanol -4.8 kcal / mol

CCC [C @ H] (C) O (2S) -2-pentanol -4.8 kcal / mol

C [C @@ H] (CCO) CO0 (2S) -2-methyl-1,4-butanediol -4.9 kcal / mol -5.0 kcal / mol

CC (C) (CCO) O 2-methyl-2,4-butanediol -4.9 kcal / mol -5.1 kcal / mol

CCC (CO) (CO) CO Trimethylolpropane -5.2 kcal / mol -5.3 kcal / mol

In one example, the step of administering to a patient having one or more conditions includes 3,3-dimethyl-1-butanol (DMB) comprising at least one of the following (eg, one or more) to a patient having one or more conditions: Administration may include administering a therapeutically effective amount of a compound comprising an analog: 2-ethyl-1-butanol, (2R) -3,3-dimethyl-1,2-butanediol; (2S) -3,3-dimethyl-1,2-butanediol; (2S) -4-methyl-2-pentanol; (2S) -3-methyl-2 butanol; (2R) -4-methyl-2-pentanol; (2R) -3-methyl-2-butanol; (2S) -2-pentanol; (2S) -2-methyl-1,4-butanediol; 2-methyl-2,4-butanediol; Trimethylolpropane; And their pharmaceutically acceptable forms (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). However, compounds comprising 3,3-dimethyl-1-butanol (DMB) analogs can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner (eg, any (To affect the appropriate target).

Compounds for inhibiting (and / or otherwise affecting) the CutC enzyme are one or more compounds for inhibiting the CutC enzyme of microorganisms from Firmicutes (Moon), such as Table 2 (e.g., above The compound may contain specificity for the CutC enzyme from a microorganism from Firmicutes , the compound does not bind to the CutC enzyme from a microorganism from Proteobacteria or binds with low affinity; Each of the compounds may exhibit a subset of molecules that exert the same binding energy, eg, having a structure similar to that of the compound; wherein the compound is, as indicated by the binding energy value, for the CutC enzyme. , Choline or higher affinity than DMB). May comprise a case which may include one or more of the compounds (and / or general (generally) compound) that may hamhal.

Pirmicutes ( Firmicutes From  Microbial CutC  Examples of compounds (eg molecules) that can bind to enzymes (eg Pirmicutes - C0D5P1 CutC  enzyme) rescue SMILES code IUPAC nomenclature Binding energy ( CutC  For enzymes, Pirmicutes )

COc1ccc (cc1) CCC = O 3- (4-methoxyphenyl) propanal -4.9 kcal / mol

C [C @ H] (Cc1cccnc1) [NH3 +] 1- (3-pyridinyl) -2-propanamine -5.0 kcal / mol

CC [C @@ H] (C) c1ccccc1O 2-[(2R) -2-butanyl] phenol 2R) -2-Butanyl] phenol -5.2 kcal / mol

CCCc1ccc (cc1) C (= O) O 4-propylbenzoic acid -5.3 kcal / mol

C [C @@ H] (COCc1ccccc1) O (2S) -1- (benzyloxy) -2-propanol -5.4 kcal / mol

COC (= O) CCc1ccc (cc1) O Methyl 3- (4-hydroxyphenyl) propanoate -5.5 kcal / mol

C [C @@] (Cc1ccccc1) (C (= O) O) [NH3 +] α-methylphenylalanine -5.6 kcal / mol

CC (C) (C) C (c1ccccc1) O
2,2-dimethyl-1-phenyl-1-propanol -5.7 kcal / mol

COC (= O) [C @@ H] (c1ccccc1) O Methyl (2R) -hydroxy (phenyl) acetate -5.8 kcal / mol

c1ccc (cc1) [C @@ H] 1CCC [NH2 +] 1 (2S) -2-phenylpyrrolidinium -5.9 kcal / mol

Cc1c (noc1N) c1ccccc1 4-methyl-3-phenyl-1,2-oxazole-5-amine -6.0 kcal / mol

c1cc (ccc1c1ccc (cc1) N) N 4,4'-biphenyldiamine -6.1 kcal / mol

Cc1ccc (cc1) c1ccccc1C # N 4'-methyl-2-biphenylcarbonitrile -6.2 kcal / mol

c1ccc (cc1) c1ccc (cc1) O 4-biphenylol -6.3 kcal / mol

Cc1ccc (cc1) c1cc (on1) CCO 2- [3- (4-methylphenyl) -1,2-oxazol-5-yl] ethanol -6.4 kcal / mol

c1ccc (cc1) c1ccc (cc1) C (= O) N 4-biphenylcarboxamide -6.5 kcal / mol

C # Cc1ccc (cc1) c1ccccc1 4-ethynylbiphenyl -6.6 kcal / mol

Cc1ccc (cc1) c1nc ([nH] n1) N 5- (4-methylphenyl) -1H-1,2,4-triazole-3-amine -6.7 kcal / mol

Cc1ccc (cc1) c1cc ([nH] n1) N 5- (4-methylphenyl) -1H-pyrazol-3-amine -6.8 kcal / mol

c1cc (c (cc1O) O) O 4-hydroxycatechol -6.9 kcal / mol

c1ccc (cc1) c1cc (n [nH] 1) C (= O) NN 3-phenyl-1H-pyrazole-5-carbohydrazide -7.0 kcal / mol

Cc1ccc (cc1O) O 4-methyl-1,3-benzenediol -7.1 kcal / mol

In one example, the step of administering to a patient having one or more conditions comprises administering to a patient having one or more conditions a therapeutically effective amount of a compound to inhibit the CutC enzyme of a microorganism from Firmicutes (Moon). Can include, wherein the compound can include at least one of the following (eg, any one or more, etc.): 3- (4-methoxyphenyl) propanal; 1- (3-pyridinyl) -2-propanamine; 2-[(2R) -2-butanyl] phenol; 4-propylbenzoic acid; (2S) -1- (benzyloxy) -2-propanol; Methyl 3- (4-hydroxyphenyl) propanoate; α-methylphenylalanine; 2,2-dimethyl-1-phenyl-1-propanol; Methyl (2R) -hydroxy (phenyl) acetate; (2S) -2-phenylpyrrolidinium; 4-methyl-3-phenyl-1,2-oxazole-5-amine; 4,4'-biphenyldiamine;4'-methyl-2-biphenylcarbonitrile;4-biphenylol; 2- [3- (4-methylphenyl) -1,2-oxazol-5-yl] ethanol; 4-biphenylcarboxamide; 4-ethynylbiphenyl; 5- (4-methylphenyl) -1H-1,2,4-triazole-3-amine; 5- (4-methylphenyl) -1H-pyrazol-3-amine; 4-hydroxycatechol; 3-phenyl-1H-pyrazole-5-carbohydrazide; 4-methyl-1,3-benzenediol; And pharmaceutically acceptable forms thereof (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). However, compounds for inhibiting the CutC enzyme of a microorganism from Firmicutes can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner (eg, any (To affect the appropriate target).

Compounds for inhibiting (and / or otherwise affecting) the CutC enzyme are one or more compounds for inhibiting the CutC enzyme of a microorganism from Proteobacteria (Moon), such as Table 3 (e.g., above The compound may contain specificity for the CutC enzyme from a microorganism from Proteobacteria , the compound does not bind to the CutC enzyme from a microorganism from Proteobacteria or binds with low affinity; Each of the compounds may exhibit a subset of molecules that exert the same binding energy, eg, having a structure similar to that of the compound; wherein the compound is, as indicated by the binding energy value, for the CutC enzyme. Likewise, any one included in choline or DMB, which may contain a higher affinity) It may include a case that may include one or more compounds (and / or generically (generally) compound) that may include the above compounds.

From Proteobacteria  Microbial CutC  Examples of compounds (eg molecules) that can bind to enzymes (eg Proteobacteria -B4EYG1 CutC  enzyme) rescue SMILES code IUPAC nomenclature Binding energy (for CutC enzyme, Proteobacteria )

C (C [NH3 +]) C [NH2 +] CCO N- (2-hydroxyethyl) -1,3-propanediaminium -4.8 kcal / mol

CC (C) (CCO) OC 3-methoxy-3-methylbutanol -4.9 kcal / mol

c1cnccc1C [NH3 +] 4-pyridinylmethaneaminium -5.0 kcal / mol

CNc1cccnc1 N-methyl-3-pyridinamine -5.1 kcal / mol

COc1ccccn1 2-methoxypyridine -5.2 kcal / mol

Cc1cc (cnc1) N 5-methyl-3-pyridinamine -5.3 kcal / mol

Cc1ccncc1C [NH3 +] 1- (4-methyl-3-pyridinyl) methanamine -5.4 kcal / mol

Cc1cc (cc (c1) C) C Mesitylene -5.5 kcal / mol

c1ccc (cc1) / C = NO (E) -Benzaldoxime -5.6 kcal / mol

CC (C) [C @ H] (C (C) (C) CO) O (3R) -2,2,4-trimethyl-1,3-pentanediol -5.7 kcal / mol

C1C [C @@ H] 2C [C @ H] 1C [N @@ H +] 2CC (= O) O (1R, 4R) -2-azabicyclo [2.2.1] hept-2-ylacetic acid -5.8 kcal / mol

CC (= O) c1cccc (c1) O 3-acetylphenol -5.9 kcal / mol

c1cc (cc (c1) O) C (= O) O 3-hydroxybenzoic acid -6.0 kcal / mol

c1cc2cc [nH] c2c (c1) CO  1H-indole-7-ylmethanol -6.1 kcal / mol

C = Cc1cccc (c1) N 3-vinyl aniline -6.2 kcal / mol

C1 [C @ H] 2C [C @ H] 3C [C @@ H] 1C [C @@] (C2) (C3) N = C = O (3s, 5s, 7s) -1-isocyanato adamantine (isocyanato adamantane) -6.3 kcal / mol

C [C @@] 1 ([C @@ H] 2C [C @@ H] (C2 (C) C) CC1 = O) O (1R, 2S, 5R) -2-hydroxy-2,6,6-trimethylbicyclo [3.1.1] heptan-3-one -6.4 kcal / mol

CC1 ([C @ H] 2CCC (= C) [C @@ H] 1C2) C (-)-β-pinene -6.5 kcal / mol

c1ccc2c (c1) c ([nH] c2N) N 2H-isoindole-1,3-diamine -6.6 kcal / mol

C1 [C @ H] 2C [C @ H] 3C [C @@ H] 1C [C @@] (C2) (C3) O (3s, 5s, 7s) -1-adamantanol -6.7 kcal / mol

C1C [C @ H] 2C [C @@ H] 1 [C @ H] ([C @ H] 2 [NH3 +]) CO (3-aminobicyclo [2.2.1] hep-2-yl) methanol -6.8 kcal / mol

c1cc (cc (c1) O) CN [NH3 +] 3- (hydrazinomethyl) phenol -6.9 kcal / mol

C1CC [C @@ H] ([C @@ H] (C1) C (= O) N) [NH3 +] (1S, 2R) -2-carbamoylcyclohexaneaminium -7.0 kcal / mol

C [C @] 12CC [C @ H] (C1) C (C2 = O) (C) C (1S, 4R) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one -7.1 kcal / mol

C [C @@] 12CC [C @@ H] (C1) C (C2 = O) (C) C (1R, 4S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one -7.4 kcal / mol

In one example, the step of administering to a patient with one or more conditions comprises administering to a patient with one or more conditions a therapeutically effective amount of a compound to inhibit the CutC enzyme of a microorganism from Proteobacteria (Moon). And may include at least one of the following (eg, any one or more, etc.): N- (2-hydroxyethyl) -1,3-propanedianium; 3-methoxy-3-methylbutanol; 4-pyridinylmethaneaminium; N-methyl-3-pyridinamine; 2-methoxypyridine; 5-methyl-3-pyridinamine; 1- (4-methyl-3-pyridinyl) methanamine; Mesitylene; (E) -benzaldoxime '(3R) -2,2,4-trimethyl-1,3-pentanediol; (1R, 4R) -2-azabicyclo [2.2.1] hept-2-ylacetic acid; 3-ACETylphenol; 3-hydroxybenzoic acid; 1H-indole-7-ylmethanol; 3-vinyl aniline; (3s, 5s, 7s) -1-isocyanatoadamantine (isocyanatoadamantane); (1R, 2S, 5R) -2-hydroxy-2,6,6-trimethylbicyclo [3.1.1] heptan-3-one; (-)-β-pinene; 2H-isoindole-1,3-diamine; (3s, 5s, 7s) -1-adamantanol; (3-aminobicyclo [2.2.1] hep-2-yl) methanol; 3- (hydrazinomethyl) phenol; (1S, 2R) -2-carbamoylcyclohexaneaminium; (1S, 4R) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; (1R, 4S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; And their pharmaceutically acceptable forms (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). However, compounds for inhibiting the CutC enzyme of microorganisms from Proteobacteria (moon) can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner (e.g. For example, to affect any suitable target).

Compounds for inhibiting (and / or otherwise affecting) the CutC enzyme include Firmicutes (moon) and Proteobacteria (moon) (e.g., first from Pyrmicutes ) One or more compounds for inhibiting a microorganism's CutC enzyme from the microorganism's CutC enzyme, as well as a second microorganism's CutC enzyme from proteobacteria, such as Table 4 (e.g., binding to a CutC enzyme related to Pyrmicustes) , And a compound that binds to the CutC enzyme associated with the proteobacteria; for example, the compound inhibits the product of TMA by CutC in a set of microorganisms across different taxa, spanning, for example, Pyr Mycus and Proteobacteria. Where possible; each compound exerts the same binding energy, e.g., having a structure similar to that of the compound, Ruler; wherein the compound is any one or more compounds included in the CutC enzyme, which may contain a higher affinity than choline or DMB, as indicated by the binding energy value). It may include cases that may include one or more compounds (and / or generically) compounds that may be included.

Proteobacteria  And From Pyrmicutes  Microbial CutC  Examples of compounds (eg molecules) that can bind to enzymes rescue SMILES Cog IUPAC nomenclature Binding energy (for CutC enzyme, proteobacteria) Binding energy (for CutC enzyme, Pyrmicutes)

CC1 (CC [NH2 +] CC1) C (= O) OC Methyl 4-methyl-4-piperidinecarboxylate -4.8 kcal / mol -4.8 kcal / mol

CCCCCCC (= O) OC Methyl heptanoate -4.9 kcal / mol -4.9 kcal / mol

Cc1cccnn1 3-methylpyridazine -5.0 kcal / mol -5.0 kcal / mol

Cc1c (onc1N) C 4,5-dimethyl-1,2-oxazole-3-amine -5.1 kcal / mol -5.1 kcal / mol

c1ccc (c (c1) O) OCCO 2- (2-hydroxyethoxy) phenol -5.2 kcal / mol -5.2 kcal / mol

c1cc (cnc1) C [NH2 +] CCO 2-hydroxy-N- (3-pyridinylmethyl) ethanaminium -5.3 kcal / mol -5.3 kcal / mol

c1ccc (cc1) CCCO 3-phenyl-1-propanol -5.4 kcal / mol -5.4 kcal / mol

C [C @ H] (CCCC (C) C) O (2R) -6-methyl-2-heptanol -5.5 kcal / mol -5.5 kcal / mol

c1ccc (cc1) OCC (= O) NN 2-phenoxyacetohydrazide -5.6 kcal / mol -5.6 kcal / mol

CCCC CCCC (= O) NO N-hydroxyoctanamide -5.7 kcal / mol -5.7 kcal / mol

C1CC (C1) C (= O) NN Cyclobutanecarbohydrazide -5.8 kcal / mol -5.8 kcal / mol

c1ccc (cc1) NN Phenylhydrazine -5.9 kcal / mol -5.9 kcal / mol

C1 [C @@ H] 2C = C [C @ H] 1NC2 = O (1S, 4R) -2-azabicyclo [2.2.1] hep-5-en-3-one -6.0 kcal / mol -6.0 kcal / mol

c1ccc (c (c1) C (= O) N) O Salicylamide -6.1 kcal / mol -6.1 kcal / mol

C1 [C @@ H] 2C [C @@ H] 3C [C @ H] 1C [C @ H] (C2) C3 Adamantane -6.2 kcal / mol -6.2 kcal / mol

C1C [C @@ H] 2C [C @ H] (C1) C [NH2 +] C2  3-azabicyclo [3.3.1] Noneine -6.4 kcal / mol -6.4 kcal / mol

Cc1ccccc1 / C (= N / O) / N  N-hydroxy-2-methylbenzenecarboximideamide -6.5 kcal / mol -4.9 kcal / mol

CC1 ([C @ H] 2CC [C @ H] (C2) C1 = C) C (-)-Kampen -6.6 kcal / mol -5.4 kcal / mol

C1 [C @ H] 2C [C @@ H] ([C @@ H] 1C = C2) CO (1S, 2S, 4S) -Bicyclo [2.2.1] hept-5-en-2-ylmethanol -6.7 kcal / mol -6.1 kcal / mol

C1C = C [C @ H] 2 [C @ H] 1 [C @ H] 1C [C @@ H] 2C = C1 Dicyclopentadiene -6.8 kcal / mol -5.0 kcal / mol

C1C [C @ H] 2C [NH2 +] C [C @@ H] 1 [C @@ H] 2O (8-anti) (anti) -3-azabicyclo [3.2.1] octane-8-ol -5.8 kcal / mol -6.9 kcal / mol

C1C = C [C @@ H] 2 [C @ H] 1 [C @ H] 1C [C @@ H] 2C = C1 (1R, 2S, 6R, 7S) -Tricyclo [5.2.1.02,6] deca-3,8-diene -7.0 kcal / mol -6.0 kcal / mol

In one example, the step of administering to a patient with one or more conditions is therapeutic for inhibiting the microbial CutC enzyme from Firmicutes and Proteobacteria (Moon) to a patient with one or more conditions. And administering an effective amount of a compound, wherein the compound may include at least one of the following (eg, any one or more, etc.): methyl 4-methyl-4-piperidinecarboxylate ; Methyl heptanoate; 3-methylpyridazine; 4,5-dimethyl-1,2-oxazol-3-amine; 2- (2-hydroxyethoxy) phenol; 2-hydroxy-N- (3-pyridinylmethyl) ethanaminium; 3-phenyl-1-propanol; (2R) -6-methyl-2-heptanol; 2-phenoxyacetohydrazide; N-hydroxyoctanamide; Cyclobutanecarbohydrazide; Phenylhydrazine; (1S, 4R) -2-azabicyclo [2.2.1] hep-5-en-3-one; Salicylamide; Adamantane; 3-azabicyclo [3.3.1] nonane; N-hydroxy-2-methylbenzenecarboximideamide; (-)-Campen; (1S, 2S, 4S) -bicyclo [2.2.1] hept-5-en-2-ylmethanol; Dicyclopentadiene; (8-anti) (anti) -3-azabicyclo [3.2.1] octane-8-ol; (1R, 2S, 6R, 7S) -tricyclo [5.2.1.02,6] deca-3,8-diene; Pharmaceutically acceptable forms thereof (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). In one example, a compound (e.g., proteobacteria) comprising different binding affinity (and / or other suitable interaction parameters) for the CutC enzyme depending on the association of the CutC enzyme for a given taxonomic group. Microbial CutC Enzymes from; Microbial CutC Enzymes from Pyrmicus; As such, different applications can be made possible. However, the compounds for inhibiting the CutC enzyme of microorganisms from Pyrmicus (moon) and Proteobacteria (moon) can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner. Yes (for example, to affect any suitable target).

The step of administering one or more compounds inhibits CntA enzymes, such as CntA enzymes of microorganisms from at least one of Pyrmicutes (moon), Proteobacteria (moon), and / or other suitable taxonomic groups. (And / or otherwise affect) administering one or more compounds (eg, a therapeutically effective amount; etc.). In one example, L-carnitine (eg, substrate of CntA enzyme, etc.) can bind to the active site of CntA enzyme to promote the production of TMA, TMAO and / or derivatives thereof, where L-carnitine is metabolized A compound that inhibits (and / or otherwise affects) CntA enzymes, and / or compounds that have an associated condition, a nutritional-related condition (e.g., a weight-related condition, a hyperglycemic-related condition, etc.) and / or It may be related to other suitable conditions (eg, cause, correlation, impact, etc.), such as when it is possible to reduce the effects of L-carnitine and / or CntA enzymes.

Compounds for inhibiting (and / or otherwise affecting) CntA enzymes (eg, associated with microorganisms from at least one of Pyrmicus and Proteobacteria) may include one or more L-carnitine analogs (eg, It may include a CntA enzyme with an affinity equal to or greater than that of L-carnitine, for example, for a CntA enzyme belonging to Pyrmicus and / or Proteobacteria, etc.). In one example, L-carnitine analogs and / or other suitable compounds can bind to the CntA enzyme to competitively inhibit the binding of L-carnitine to the CntA enzyme (e.g., substrate and inhibitor bind to the active site simultaneously) If not, the inhibition of competition here may promote reduced production of TMA, TMAO and / or derivatives thereof). In one example, an L-carnitine analog (and / or a generic compound) can include any one or more compounds included in Table 5.

Proteobacteria  And / or From Pyrmicutes  Microbial CntA  Examples of L-carnitine analogs capable of binding to enzymes rescue SMILES code IUPAC nomenclature Binding energy (For CntA enzyme, proteobacteria) Binding energy (for CntA enzyme, Pyrmicutes)

C [NH2 +] [C @@ H] (CCC (= O) O) C (= O) O N-methylglutamic acid -4.9 kcal / mol

C1CC [NH +] (C1) CCCC (= O) O 4- (1-pyrrolidinyl) butanoic acid -5.1 kcal / mol

CC1 (CC [NH2 +] CC1) C (= O) O 4-methyl-4-piperidinecarboxylic acid -4.7 kcal / mol -5.0 kcal / mol

C1C [NH2 +] CCC1C (= O) O Isonifecotic acid -4.9 kcal / mol

In one example, the step of administering to a patient with one or more conditions is a therapeutically effective amount of a compound comprising an L-carnitine analog comprising at least one of the following (e.g., one or more) to a patient with one or more conditions: It may include administering: N-methyl glutamic acid; 4- (1-pyrrolidinyl) butanoic acid; 4-methyl-4-piperidinecarboxylic acid; Isonifecotic acid; And their pharmaceutically acceptable forms (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). However, compounds comprising L-carnitine analogs can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner (eg, to affect any suitable target). .

Compounds for inhibiting (and / or otherwise affecting) CntA enzymes are one or more compounds for inhibiting CntA enzymes of microorganisms from Firmicutes (Moon), such as Table 6 (e.g., above The compound may contain specificity for CntA enzymes from microorganisms from Firmicutes , the compound does not bind to CntA enzymes from microorganisms from Proteobacteria or binds with low affinity; Each of the compounds may exhibit a subset of molecules that exert the same binding energy, eg, having a structure similar to that of the compound; wherein the compound is, as indicated by the binding energy value, for the CntA enzyme. , May include a higher affinity than L-carnitine). It may include a case that may include one or more compounds (and / or generically) compounds that can.

From Pyrmicutes  Microbial CntA  Examples of compounds (eg molecules) that can bind to enzymes (eg Pirmicutes -J3B3E2 CntA  enzyme) rescue SMILES code IUPAC nomenclature Binding energy ( CntA  For enzymes, Pirmicutes )

CCCc1ccccc1 N-propylbenzene -5.8 kcal / mol

CCNc1cccc [nH +] 1 N-ethyl-2-pyridinamine -5.7 kcal / mol

CCCN1C [C @ H] (CC1 = O) [NH3 +] (4R) -4-amino-1-propyl-2-pyrrolidinone -5.6 kcal / mol

Cc1cc (ccc1N) N 2,5-diaminotoluene -5.5 kcal / mol

CCOc1ccccc1 Ethyl phenyl ether -5.4 kcal / mol

c1ccc (cc1) OC # N Phenyl cyanate -5.3 kcal / mol

CC (= O) C [C @@ H] 1CCC = C1 1- (2-cyclopenten-1-yl) acetone -5.2 kcal / mol

Cc1ccc [nH +] c1N 2-amino-3-methylpyridinium -5.1 kcal / mol

c1cc (cnc1) / C = N / O E-pyridine-3-aldoxime -5.0 kcal / mol

C1CCC (CC1) NC = O N-cyclohexylformamide -4.9 kcal / mol

CCC / C = C (\ C) / C (= O) O 2-methyl-2-hexenic acid -4.8 kcal / mol

CCCC (CCC) [NH3 +] 4-heptanaminium -4.7 kcal / mol

In one example, the step of administering to a patient having one or more conditions comprises administering to a patient having one or more conditions a therapeutically effective amount of a compound to inhibit the CntA enzyme of a microorganism from Firmicutes (Moon). Can include, wherein the compound can include at least one of the following (eg, any one or more, etc.): N-propylbenzene; N-ethyl-2-pyridinamine; (4R) -4-amino-1-propyl-2-pyrrolidinone; 2,5-diaminotoluene; Ethyl phenyl ether; Phenyl cyanate; 1- (2-cyclopenten-1-yl) acetone; 2-amino-3-methylpyridinium; E-pyridine-3-aldoxime; N-cyclohexyl formamide; 2-methyl-2-hexenic acid (hexenoic acid); 4-heptanaminium; And pharmaceutically acceptable forms thereof (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). However, compounds for inhibiting the CntA enzyme of microorganisms from Firmicutes can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner (e.g., any (To affect the appropriate target).

Compounds for inhibiting (and / or otherwise affecting) CntA enzymes are one or more compounds for inhibiting CntA enzymes of microorganisms from Proteobacteria (Moon), such as Table 7 (e.g., above The compound may contain specificity for the CntA enzyme from a microorganism from Proteobacteria , the compound does not bind to CntA enzyme from a microorganism from Proteobacteria or binds with low affinity; Each of the compounds may exhibit a subset of molecules that exert the same binding energy, eg, having a structure similar to that of the compound; wherein the compound is, as indicated by the binding energy value, for the CntA enzyme. Likewise, any one included in a) that may contain a higher affinity than L-carnitine May comprise a case which may include one or more of the compounds (and / or general (generally) compound) that may include on the compound.

From Proteobacteria  Microbial CntA  Examples of compounds (eg molecules) that can bind to enzymes (eg Proteobacteria -L1LUC3 CntA  enzyme) rescue SMILES code IUPAC nomenclature Binding energy ( CntA  For enzymes, Proteobacteria )

C (C (= O) O) [C @] 1 ([C @@ H] (O1) C (= O) O) C (= O) O 3,4-anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid -4.8 kcal / mol

C (CO) [NH +] (CC (= O) O) CC (= O) O 2,2 '-[(2-hydroxyethyl) imino] diacetic acid -4.6 kcal / mol

C (c1nn [nH] n1) C (= O) O 1H-tetrazol-5-ylacetic acid -4.5 kcal / mol

CC (= O) C (C (= O) C) C (= O) C Diacetylacetone -4.4 kcal / mol

C [C @@ H] (C (= O) O) OC (= O) C (2S) -2-acetoxy propanoic acid -4.3 kcal / mol

In one example, the step of administering to a patient having one or more conditions comprises administering to a patient having one or more conditions a therapeutically effective amount of a compound to inhibit the CntA enzyme of the microorganism from Proteobacteria (Moon). Can include, wherein the compound can include at least one of the following (eg, any one or more, etc.): 3,4-anhydro-3-carboxy-2-deoxy-L-threo- Pentaric acid; 2,2 '-[(2-hydroxyethyl) imino] diacetic acid; 1H-tetrazol-5-ylacetic acid; Diacetylacetone; (2S) -2-acetoxy propanoic acid; And their pharmaceutically acceptable forms (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). However, compounds for inhibiting CntA enzymes of microorganisms from Proteobacteria (moon) can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner (e.g. For example, to affect any suitable target).

Compounds for inhibiting (and / or otherwise affecting) CntA enzymes include Firmicutes (moon) and Proteobacteria (moon) (e.g., first from Pyrmicutes ) One or more compounds for inhibiting the CntA enzyme of the microorganism from the CntA enzyme of the microorganism, as well as the second microorganism's CutC enzyme from proteobacteria, etc. , And a compound that binds to a CntA enzyme associated with a proteobacteria; for example, the compound inhibits the product of TMA by CntA in a set of microorganisms across different taxa, spanning, for example, Pyrmicus and proteobacteria. Where possible; each compound exerts the same binding energy, e.g., having a structure similar to that of the compound, Ruler; wherein the compound is any one or more compounds included in the CntA enzyme, which may contain a higher affinity than L-carnitine, as indicated by the binding energy value). It may include cases that may include one or more compounds (and / or generically) compounds that may be included.

Proteobacteria  And From Pyrmicutes  Microbial CntA  Examples of compounds (eg molecules) that can bind to enzymes rescue SMILES code IUPAC nomenclature Binding energy (for CntA enzyme, Proteobacteria ) Binding energy (for CntA enzyme, Pirmicutes )

c1cc2c (cc1c1ccc3c (c1) C (= O) OC3 = O) C (= O) OC2 = O 4,4'-biphthalic anhydride -8.9 kcal / mol -8.9 kcal / mol

O = C (n1nnc2ccccc12) n1nnc2ccccc12 Bis (1H-benzotriazol-1-yl) methanone -7.9 kcal / mol -7.9 kcal / mol

c1ccc2c (c1) C (= O) c1ccc (cc1C2 = O) S (= O) (= O) O 2-anthraquinone sulfonic acid -7.8 kcal / mol -7.8 kcal / mol

c1ccc2c (c1) C (= O) N (C2 = O) c1cccc (c1) C # N 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzonitrile -7.7 kcal / mol -7.7 kcal / mol

c1ccc (cc1) c1nc2ccccc2c (= O) [nH] 1 2-phenylquinazolin-4-ol -7.6 kcal / mol -7.6 kcal / mol

c1ccc2c (c1) nc (s2) c1cc (ccc1O) N 4-amino-2- (1,3-benzothiazol-2-yl) phenol -7.5 kcal / mol -7.5 kcal / mol

c1ccc (cc1) c1c2ccccc2c (= O) [nH] n1 4-phenyl-1 (2H) -phthalazinone -7.4 kcal / mol -7.4 kcal / mol

Cc1c (cc (o1) c1ccc2c (c1) OCO2) C (= O) O 5- (1,3-benzodioxol-5-yl) -2-methyl-3-furo acid -7.3 kcal / mol -7.3 kcal / mol

c1ccc2cc (ccc2c1) [C @ H] 1CCC (= O) O1 (5R) -5- (2-naphthyl) dihydro-2 (3H) -furanone -7.2 kcal / mol -7.2 kcal / mol

Cc1cccc (c1) c1nnc (o1) CCC (= O) O 3- [5- (3-methylphenyl) -1,3,4-oxadiazol-2-yl] propanoic acid -7.1 kcal / mol -7.1 kcal / mol

C # Cc1cc2ccccc2c2c1cccc2 9-ethynylphenanthrene -6.9 kcal / mol -6.9 kcal / mol

c1cnccc1c1cc2c ([nH] 1) CCNC2 = O PHA-767491 -6.8 kcal / mol -6.8 kcal / mol

Cc1c (cccc1O) N 3-amino-2-methylphenol -6.7 kcal / mol -6.7 kcal / mol

Cc1ccc (cc1) c1ccc (o1) C (= O) O 5- (4-methylphenyl) -2-furo acid -6.6 kcal / mol -6.6 kcal / mol

Cc1ccc2c (c1) c1c (cc (s1) C (= O) O) CO2 8-methyl-4H-thieno [3,2-c] chromen-2-carboxylic acid -6.5 kcal / mol -6.5 kcal / mol

c1ccc (cc1) C (= O) Oc1cccc (c1) O Resorcinol monobenzoate -6.4 kcal / mol -6.4 kcal / mol

COc1cc (ccc1C = O) c1ccccc1 3-methoxy-4-biphenylcarbaldehyde -6.3 kcal / mol -6.3 kcal / mol

Cc1c2ccc (cc2oc (= O) c1CC (= O) O) N (7-amino-4-methyl-2-oxo-2H-chromen-3-yl) acetic acid -6.2 kcal / mol -6.2 kcal / mol

c1cc2c (cc1C (= O) C (= O) O) CCC2 2,3-dihydro-1H-inden-5-yl (oxo) acetic acid -6.1 kcal / mol -6.1 kcal / mol

c1ccnc (c1) c1cccc (c1) N 3- (2-pyridyl) aniline -6.0 kcal / mol -6.0 kcal / mol

Cc1nc ([nH] n1) c1ccc (cc1) N 4- (3-methyl-1H-1,2,4-triazol-5-yl) aniline -5.9 kcal / mol -5.9 kcal / mol

c1cc (ccc1c1ccc (cc1) N) N Benzidine -5.8 kcal / mol -5.8 kcal / mol

COc1cc (ccc1O) C [C @@ H] (C (= O) O) [NH3 +] (DL) -3-O-methyldopa -5.7 kcal / mol -5.7 kcal / mol

Cc1cc (c (nc1) N) / C = C / C (= O) OC Methyl (2E) -3- (2-amino-5-methyl-3-pyridinyl) acrylate -5.6 kcal / mol -5.6 kcal / mol

Cc1cc2cc (oc2nc1) CO (5-methylfuro [2,3-b] pyridin-2-yl) methanol -5.5 kcal / mol -5.5 kcal / mol

c1ccc2c (c1) OC [C @ H] (O2) C [NH3 +] (2R) -2,3-dihydro-1,4-benzodioxin-2-ylmethaneaminium -5.4 kcal / mol -5.4 kcal / mol

CCC (= O) O [C @ H] (C) c1ccccc1 R-phenylethyl propionate -5.3 kcal / mol -5.3 kcal / mol

CC (C) OC (= O) c1ccccc1 i-propyl benzoate -5.2 kcal / mol -5.2 kcal / mol

Cc1ccc (cc1) NC (= O) C 4-acetotoluid -5.1 kcal / mol -5.1 kcal / mol

Cc1ccc (c (c1) [C @ H] (C) [NH3 +]) C (1S) -1- (2,5-dimethylphenyl) ethanaminium -5.0 kcal / mol -5.0 kcal / mol

CC1 = CCC = C [C @ H] 1C (= O) O (1R) -2-methyl-2,5-cyclohexadiene-1-carboxylic acid -4.9 kcal / mol -4.9 kcal / mol

COC (Cc1ccccc1) OC (2,2-dimethoxyethyl) benzene -4.8 kcal / mol -4.8 kcal / mol

In one example, the step of administering to a patient with one or more conditions is therapeutic for inhibiting the CntA enzyme of microorganisms from Firmicutes and Proteobacteria (Moon) to a patient with one or more conditions. And administering an effective amount of a compound, wherein the compound may include at least one of the following (eg, any one or more, etc.): 4,4'-biphthalic anhydride; Bis (1H-benzotriazol-1-yl) methanone; 2-anthraquinone sulfonic acid; 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzonitrile .; 2-phenylquinazolin-4-ol; 4-amino-2- (1,3-benzothiazol-2-yl) phenol; 4-phenyl-1 (2H) -phthalazinone; 5- (1,3-benzodioxol-5-yl) -2-methyl-3-furo acid; (5R) -5- (2-naphthyl) dihydro-2 (3H) -furanone; 3- [5- (3-methylphenyl) -1,3,4-oxadiazol-2-yl] propanoic acid; 9-ethynylphenanthrene; PHA-767491; 3-amino-2-methylphenol; 5- (4-methylphenyl) -2-furo acid; 8-methyl-4H-thieno [3,2-c] chromen-2-carboxylic acid; Resorcinol monobenzoate; 3-methoxy-4-biphenylcarbaldehyde; (7-amino-4-methyl-2-oxo-2H-chromen-3-yl) acetic acid; 2,3-dihydro-1H-inden-5-yl (oxo) acetic acid; 3- (2-pyridyl) aniline; 4- (3-methyl-1H-1,2,4-triazol-5-yl) aniline; Benzidine; (DL) -3-O-methyldopa; Methyl (2E) -3- (2-amino-5-methyl-3-pyridinyl) acrylate; (5-methylfuro [2,3-b] pyridin-2-yl) methanol; (2R) -2,3-dihydro-1,4-benzodioxin-2-ylmethaneaminium; R-phenylethyl propionate; i-propyl benzoate; 4-acetotoluide; (1S) -1- (2,5-dimethylphenyl) ethanaminium; (1R) -2-methyl-2,5-cyclohexadiene-1-carboxylic acid; (2,2-dimethoxyethyl) benzene; And pharmaceutically acceptable forms thereof (eg, their derivatives; their pharmaceutically deliverable forms, etc.); And / or salts thereof (eg, pharmaceutically acceptable salts, etc.). In one example, a compound (e.g., proteobacteria) comprising different binding affinity (and / or other suitable interaction parameters) for the CntA enzyme depending on the association of the CntA enzyme for a given taxonomic group. CntA enzymes of microorganisms from; CntA enzymes of microorganisms from Pyrmicutes; etc.) and / or compounds having different affinity, generally, when compounds with high affinity can exert irreversible inhibition to the CntA enzyme As such, different applications can be made possible. However, the compounds for inhibiting CntA enzymes of microorganisms from Pyrmicus (moon) and Proteobacteria (moon) can be constructed in any suitable manner, and administration of such compounds can be performed in any suitable manner. Yes (for example, to affect any suitable target).

However, the compounds may be constructed in any suitable manner, and administration of one or more compounds S110 may be performed in any suitable manner.

2.2 Determination of representative sequences

Additionally or alternatively, embodiments of method 100 may include one or more targets (e.g., CutC enzymes; CntA enzymes; other enzymes; proteins; other biological targets; non-biological targets; TMA, TMAO and / or these) Enzyme associated with at least one of the derivatives of;, etc.) may comprise the step S120 of determining one or more representative sequences, which determines the representative properties of the target for use in modeling and / or experimentation to facilitate compound determination. Can do the function.

Representative sequences and / or properties include nucleic acid sequences and / or compositions; Amino acid sequence and / or composition; Amino acid sequence and / or composition; Functional properties; Structural properties (eg, multidimensional structures, etc.); Evolutionary characteristics; And / or any other suitable property.

Representative sequences and / or properties are preferably determined for one or more targets, but can additionally or alternatively be determined for one or more control molecules, compounds and / or any other suitable molecule. In one example, a representative sequence and / or property can be determined for one or more enzymes, for example, the enzyme can include at least one CutC enzyme and a CntA enzyme, and the representative sequence is Firmicutes A set of enzyme sequences for at least one taxonomic group comprising at least one of (moon) and Proteobacteria (moon).

Representative sequences and / or characteristics preferably represent one or more taxa from the microbial taxa. For example, a representative sequence can be one or more targets (e.g., Firmicutes and / or Proteobacteria (moon) and / or other suitable taxa) for one or more microbial taxa (e.g. , CutC enzyme, CntA enzyme, etc.). In one example, determining the one or more representative sequences can include:

Target sequences (e.g., of belonging microorganisms) associated with (e.g., belonging to) the target sequence (e.g., the CutC enzyme sequence) associated with each taxonomic group (e.g., both Firmicutes and Proteobacteria ) ; Generating a sequence with a network similar to CntA enzyme sequence, etc., so as to be able to determine a representative target sequence for each taxonomic group (e.g., a first representative CutC enzyme for Pyrmicus) Sequence and a second representative CutC enzyme sequence for proteobacteria; a first representative CntA enzyme sequence for Pyrmicus and a second representative CntA enzyme sequence for proteobacteria; etc.).

However, the step (S120) of determining one or more representative sequences may be performed in any suitable manner.

2.3 Model Creation

Additionally or alternatively, an embodiment of method 100 comprises generating (S130) one or more models of one or more targets (eg, protein structural models, etc.) based on one or more representative sequences of one or more targets. And may serve to model one or more targets to facilitate experimentation useful for compound determination.

The model preferably includes a protein structural model (eg, a modeling enzyme target such as a CntA enzyme and / or a CutC enzyme, etc.), but additionally or alternatively any suitable model (eg, any suitable type) It may include a modeling of, etc.). The model may include one or more computational models, any suitable number of dimensional models, non-computational models, physical models, virtual reality models, augmented reality models and / or any suitable type of model. Can be. The model can be generated using any suitable processing operations described herein and / or the artificial intelligence approach described herein.

Model generation is preferably based on a representative sequence, such that the characteristics of the representative sequence can be used as input and / or parameters for model generation. For example, model generation is a three-dimensional (3D) model (e.g. for proteins without crystallographic data). CutC enzymes from Firmicutes (e.g., Uniprot ID: C0D5P1) using a homology modeling approach (and / or any suitable modeling approach) that can facilitate the determination of (e.g. , Based on a representative sequence for CutC enzymes from microorganisms from Pyrmicus and CutC enzymes from Proteobacteria (e.g., Uniprot ID: B4EYG1) (e.g., from Proteobacteria ) And based on representative sequences for CutC enzymes from microorganisms, etc.). For example, model generation can facilitate homology modeling approaches (and / or any suitable modeling approach) that can facilitate the determination of three-dimensional (3D) models (eg, for proteins without crystallographic data, etc.). Using CntA enzymes from Pyrmicutes (e.g., Uniprot ID: J3B3E2) (e.g., based on representative sequences for CntA enzymes from microorganisms from Pyrmicutes, etc.) Comprising generating a protein structural model for both of the CntA enzymes (e.g., Uniprot ID: L1LUC3) (e.g., based on representative sequences for CntA enzymes from microorganisms from Proteobacteria, etc.) Can be.

However, the step of generating one or more models (S130) may be performed in any suitable way.

2.4 Determining interaction parameters related to controls

Additionally or alternatively, embodiments of the method 100 may include one or more control binding parameters (and / or other suitable interaction parameters, etc.) to one or more targets based on one or more experiments with one or more models and one or more control molecules. ) May be included (S140), which may function to determine properties describing interactions between one or more controls and one or more targets.

The type of binding parameter (e.g., control binding parameter; compound binding parameter, etc.) is preferably the type of binding parameter included in Table 1-8 (e.g., binding energy value, affinity energy value, etc.) But additionally or alternatively, association rates, dissociation rates, half-life of interactions (e.g. between receptor and peptide), binding constants, binding specificity, and thermodynamic related parameters (e.g. For example, enthalpy, entropy, Gibbs free energy, parameters related to the number and type of binding sites (e.g., stoichiometry), parameters related to undesirable binding (e.g. self-assembly, with other proteins) Interference, etc.) and / or any other suitable binding parameter, including any suitable binding affinity parameter. The interaction parameters preferably include binding affinity, but additionally or alternatively with respect to control molecules, compounds, targets and / or other suitable molecules and / or interactions between any combination of these molecules. Any suitable parameter can be included.

The experiments are preferably docking simulations (e.g. docking simulations using one or more models and one or more controls on one or more models, such as for the active site of one or more protein structural models for the CutC enzyme and / or CntA enzyme) Molecular binding simulations, etc.), but may additionally or alternatively include one or more of the following: other computer simulations (eg, in silico , etc.); In vitro experiments, in vivo experiments, benchtop experiments, the use of computer models and / or any other suitable experiments.

In one example, the docking simulations are different taxa (e.g., pireu ku test (Firmicutes) and / or proteosome bacteria (Proteobacteria), etc.), control the binding parameters for the choline and DMB with respect to binding of CutC enzyme of the microorganism from (e.g. For example, it can be performed to determine the binding energy value for a control molecule, etc., e.g., a different taxonomic group (e.g., a first model of the CutC enzyme from Pyrmicutes; a CutC enzyme from Proteobacteria) Can be based on performing a simulation of docking using a model of the CutC enzyme generated for the second model of the control and simulation of control molecules (eg, choline and / or DMB) binding to the generated model. In certain examples, docking simulations were performed at -3.7 kcal / mol for choline in relation to the CutC enzyme from Pyrmicutes; -4.8 kcal / mol for DMB in relation to the CutC enzyme from Pyrmicutes; -4.1 kcal / mol for choline in relation to the CutC enzyme from Proteobacteria; And with respect to the CutC enzyme from the proteobacteria, can result in a binding energy value of -5.2 kcal / mol for DMB, for example, this binding energy value compared to choline (eg, in the context of competitive inhibition Etc.) may show a greater affinity for binding to DMB.

In one example, the docking simulations are different taxa control binding parameters for L- carnitine with respect to the binding of the enzyme of the microorganism from CntA (e.g., pireu ku test (Firmicutes) and / or proteosome bacteria (Proteobacteria), etc.) (e.g. For example, it can be performed to determine the binding energy value for a control molecule, etc., e.g., a different taxonomic group (e.g., a first model of CntA enzyme from Pyrmicutes; CntA enzyme from Proteobacteria) It can be based on the performance of the docking simulation using the model of the generated CntA enzyme for the second model) and the control molecular simulation (eg, L-carnitine; DMB, etc.) binding to the generated model. In certain examples, docking simulations were performed at -4.5 kcal / mol for L-carnitine in relation to the CntA enzyme from Pyrmicus; -4.8 kcal / mol for DMB in relation to the CntA enzyme from Pyrmicutes; -4.1 kcal / mol for L-carnitine in relation to the CntA enzyme from proteobacteria; And the binding energy value of -5.2 kcal / mol for DMB in relation to the CntA enzyme from proteobacteria.

Additionally or alternatively, the docking simulation can be performed with any suitable control molecule and / or any suitable model with respect to any suitable molecule.

In an example, determining an interaction parameter associated with a control and / or a compound (eg, with respect to S150) and / or any suitable embodiment portion of method 100 (eg, representative sequence determination S110; Model generation S120); Etc.) can apply one or more of the following: feature extraction, performing pattern recognition on data, fusion of data from multiple sources, combination of values (e.g. average value, etc.), compression, transformation (e.g. digital to analog conversion, Analog-to-digital conversion), performing statistical estimation of data (e.g., usually least-squares regression analysis, non-negative least-squares regression analysis, principal components analysis, ridge regression, etc.) , Wave modulation, normalization, updating, ranking, weighting, validating, filtering (e.g. for baseline correction, data cropping, etc.), Noise reduction, smoothing, filling (e.g. gap filling), alignment, model fitting, binning, windowing, clipping, transformation, mathematical operations (e.g. differential ( derivatives), moving average, summation, subtraction, multiplication, division ), A data connection, multiplexing, de-multiplexing (demultiplexing), interpolation (interpolating), the extrapolated (extrapolating), clustering (clustering), image processing, signal processing, visualization and / or any other suitable procedure seseng process.

In an example, determining an interaction parameter associated with a control and / or a compound (eg, with respect to S150) and / or any suitable embodiment portion of method 100 (eg, representative sequence determination S110; Model generation S120); Etc.) can apply artificial intelligence approaches (e.g., machine learning approaches, etc.) that include one or more of the following: supervised learning (e.g. using logistic regression, using backpropagation neural networks, using random forests, making decisions) Tree, etc.), unsupervised learning (e.g. using the Apriori algorithm, using K-means clustering), semi-supervised learning, deep learning algorithms (e.g. neural networks, limited Boltzmann machines) (Restricted Boltzmann Machine), deep-valley network method, convolutional neural network method, cyclic neural network method, stacked auto-encoder method, etc., reinforcement learning (e.g. Q- Use learning algorithms, use time difference learning, regression algorithms (e.g., linear least squares, logistic regression, stepwise regression, multivariate adaptive regression spline) daptive regression splines, locally estimated scatterplot smoothing, etc., case-based methods (e.g., k-nearest neighbors, learning vector quantization, self-organizing maps, etc.), normalization methods (e.g., ridge regression, Least absolute shrinkage and selection operator, elastic net, etc., decision tree learning methods (e.g. classification and regression trees, iterative dichotomiser 3, C4.5, CHAID (Chi-) squared Automatic Interaction Detection (decision stump), random forest, multivariate adaptive regression spline, GBMs (Gradient Boosting Machines), etc., Bayesian method (e.g. naive Bayes, average day) -One-dependence estimators, Bayesian belif networks, etc., kernel methods (e.g., support vector machines, radial-based functions, linear discriminant analysis, etc.), clustering methods (e.g., k- Fungal clustering, maximizing expected values, etc., related rule learning algorithms (e.g., Apriori algorithm, Eclat algorithm, etc.), artificial neural network models (e.g., Perceptron method, back-propagation) ) Method, Hopfield network method, self-organizing instruction method, learning vector quantization method, etc., dimension reduction method (e.g., principal component analysis, partial least square regression analysis, Sammon mapping, multidimensional scaling) , Projection pursuit, etc., ensemble method (e.g. boosting, bootstrapped aggregation, AdaBoost, stacked generalization, progressive boosting machine method, random forest method, etc.) and / or Or any suitable artificial intelligence approach.

 The control molecule preferably comprises one or more of choline, DMB and / or L-carnitine, but any suitable substrate that binds to any suitable target (eg, a substrate that binds to the CutC enzyme and / or CntA enzyme). , Suitable molecules associated with any suitable target and / or condition and / or any suitable molecule may additionally or alternatively be included.

However, the step (S140) of determining the interaction parameters related to the one or more control can be performed in any suitable way.

2.5 Determination of interaction parameters related to compounds

Additionally or alternatively, embodiments of the method 100 can affect one or more targets, such as a library of one or more models and compounds (eg, the ability to inhibit the CutC enzyme and / or CntA enzyme). Determining the compound binding parameters (and / or other suitable interaction parameters, etc.) based on the set of experiments using (with S150), which may include one or more compounds (e.g., potential compounds, etc.) And one or more targets.

Compound binding parameters are preferably determined for a library of compounds comprising any suitable number of compounds. Determining a library of compounds is any suitable parameter (e.g., similarity to structure, number of atoms and / or other suitable properties of the control molecule, molecules naturally associated with one or more targets and / or Other suitable molecules; database of molecules; number of compounds, type of target, type of condition, molecule that does not violate the Lipinski pharmacopoeia rule, etc.). In one example, determining a library of compounds is a number similar to (eg, within a threshold) the number of atoms of choline, DMB and / or L-carnitine (eg, within the limits of 28 atoms, etc.). It may include selecting only a compound having an atom of. In certain examples, a library of compounds may include about 24,000 molecules, but may include any suitable number of molecules.

The step of determining compound binding parameters and / or other interaction parameters is preferably, for example, using one or more generated models (e.g., CutC and CntA enzyme models for Pyrmicutes and Proteobacteria). It is based on a set of experiments (eg, the type of experiment described in connection with S140), such as based on docking simulation and binding simulation with compounds in relation to the model above.

Determination of compound binding parameters can be used to determine binding parameters included in Tables 1-8.

Determining the compound binding parameters can be performed in the same, similar, similar, or different ways of determining the control binding parameters.

However, step S150 of determining the interaction parameters associated with one or more compounds can be performed in any suitable way.

2.6 Identifying compounds

Additionally or alternatively, an embodiment of method 100 may include step S160 of identifying one or more compounds based on one or more control binding parameters and a set of compound binding parameters (eg, from a library of compounds, etc.). Which may be at least for treating patients with conditions associated with at least one of trimethylamine (TMA), trimethylamine N-oxide (TMAO) and derivatives thereof and / or for treating patients with any suitable condition. It can function to identify one compound.

The step of identifying a compound is preferably based on a comparison between one or more control binding parameters and a set of compound binding parameters (eg, compound library filtering for compounds corresponding to compound binding parameter parameters greater than one or more control binding parameters) Etc). Additionally or alternatively, the step of identifying the compound may be based on the control binding parameter and the compound binding parameter in any suitable manner, and / or interaction parameters associated with one or more control molecules and / or with the compound. It can be based on any suitable interaction parameter involved.

In one example, the step of identifying the compound is from a library of compounds (e.g., within a limit of 28 atoms, selection based on atomic number similarity to choline and / or DMB, etc.), binding affinity to the CutC enzyme over choline. And selecting a compound having the same or greater value (eg, represented by a binding energy value, etc.). In one example, a compound (e.g., having the same or greater binding affinity to the CutC enzyme than choline, etc.) is non-invasive (e.g., non-violation, etc.) to the Lipinski pharmacopoeic rule. It can be filtered based on (eg, further filtration, etc.), for example, molecular weight <500 Daltons, H-linked donor number <5, H-linked receptor number <10, N and O atom number <15 , Distribution coefficient between log P range -2 and 5, can include the number of rotatable bonds <10, the number of rings <10. In one example, a compound (e.g., a binding affinity for a CutC enzyme greater than or equal to choline and / or does not violate the Ripinski pharmacopoeic rule, etc.) is any atom wherein the molecule is different from the CHON atom It may be filtered (eg, additional filtration, etc.) in the case of including.

In one example, the step of identifying a compound is greater than L-carnitine from a compound library (e.g., within the limit of 28 atoms, based on atomic number similarity with choline, DMB and / or L-carnitine, etc.). And selecting a compound having the same or greater binding affinity for the CntA enzyme (eg, expressed as a binding energy value, etc.). In one example, a compound (e.g., having the same or greater binding affinity for the CntA enzyme than L-carnitine, etc.) has a non-infringing (e.g., non-violation) Lipinski pharmacopoeic rule. Etc.) can be filtered (eg, additional filtration, etc.), e.g., molecular weight <500 Daltons, number of H-linked donors <5, number of H-linked receptors <10, number of N and O atoms <15, distribution coefficient between log P ranges -2 and 5, can include the number of rotatable bonds <10, the number of rings <10. In one example, the compound (e.g., the binding affinity for the CntA enzyme is greater than or equal to L-carnitine and / or does not violate the Ripinski pharmacopoeic rule, etc.), if the molecule is different from the CHON atom It may be filtered (eg, additional filtration, etc.) when it contains atoms of.

In the Examples, if these criteria (and / or any suitable criteria) are applied when determining a compound, the DMB analog (e.g., Tanimoto coefficient> = 0.8, and Pyrmicutes and Pro) L-carnitine analogs (e.g., Tanimoto coefficient), e.g., with binding affinity equal to or greater than DMB for the CutC enzyme from Thebacteria; as shown in Table 1; etc.) > = 0.7 and included in Tables 1 to 8, such as having a binding affinity equal to or greater than L-carnitine for CutC enzymes from Pyrmicus and Proteobacteria; as shown in Table 4; etc.) Any suitable compound can be derived.

The identified compounds can preferably be used to treat patients with one or more conditions associated with at least one of TMA, TMAO and derivatives thereof and / or to treat patients with any suitable condition. For example, the identified compounds can be used to administer a therapeutically effective amount of one or more compounds (eg, with respect to S110). Additionally or alternatively, the identified compounds can be used for any suitable purpose.

However, step S160 for identifying the compound can be performed in any suitable way.

2.7 Compound Validation (validating)

Additionally or alternatively, an embodiment of the method 100 may include the step (S170) of validating (verifying) one or more compounds, which may be used to experimentally verify and / or otherwise test one or more compounds. Can function.

Any suitable compound described herein can be verified (eg, experimentally tested, etc.). The compound can preferably be verified in relation to its effect on one or more targets (eg, CutC enzyme, CntA enzyme, etc.). For example, a compound inhibits the conversion of choline (e.g., in the context of a CutC enzyme, etc.) or L-carnitine (e.g., in connection with a CntA enzyme) to trimethylamine (TMA) by an intestinal microbiota. This can be verified in relation to the ability of the compound to perform. As such, the compounds can be validated with respect to their ability to treat one or more conditions associated with at least one of trimethylamine (TMA), trimethylamine N-oxide (TMAO), and derivatives thereof. However, any suitable molecule described herein can be verified for a suitable purpose, for example, by applying any one or more techniques described herein.

In the examples, experiments are performed using cultivation of bacterial strains producing CutC / CutD or CntA / CntB enzymes. For example, Acinetobacter baumanii (Proteobacteria, aerobic, CntA / CntB production), Proteus mirabilis (Proteobacteria, anaerobic, CutC / CutD Production), Sporosarcina newyorkensis DSM 23540 (Firmicutes, CntA / CntB production, aerobic) and / or Streptococcus dysgalactiae DSM23147 (Pyrmicutes, CutC) / CutD production, anaerobic).

In one example, the experimental setup includes evaluating gradual consumption of choline and / or L-carnitine and / or gradual production of TMA. In a specific example, to quantify the production of (TMA), cultures are set up in triplicates in cell culture flasks using medium supplemented with carnitine or choline (as appropriate) as the sole carbon source; Samples were taken from each flask at different time points (eg, t = 0, 4, 8, 12, 24 and 48 hours; any suitable time point); An optical density at 600 nm was obtained for each sample; And TMA, carnitine and / or choline are quantified for each sample (eg, corresponding to different time points, etc.). L-carnitine and choline can be quantified in each sample using standard quantitation kits (e.g. MAK056 and MAK063, Sigma-Aldrich). TMA quantification can be performed using cation exchange ion chromatography equipped with a separation column and a conductivity detector.

Additionally or alternatively, CutC or CntA TMA lyase activity can be quantified in vitro, for example by incubating: cell lysate (typically ~ 3 mg protein), isolated enzyme ( Typically ~ 30 μg protein), cultured live microorganisms (OD _600nm ~ 1.0), and / or over cecal lysate with d9-labeled synthetic substrate (100 μM for 10-16 hours, choline or L -Carnitine). In this case, TMA degrading enzyme activity can be monitored by quantifying d9-TMA production by LC / MS / MS analysis. Additionally or alternatively, cation-exchange ion chromatography can be used to detect TMA production from the supernatant of cultured cells. However, any suitable quantitative technique can be applied, for example for the verification of one or more compounds.

In a specific example, the dose of the control compound DMB to confirm a decrease in TMA production in each culture, using the baseline obtained for consumption of L-carnitine and / or choline and / or production of TMA. Response curves (eg, after incubation for 10-16 hours) can be obtained; And culturing the compound in a corresponding intact cell culture using L-carnitine and / or choline as substrates at different concentrations (e.g., 20, 40, 60, 80, 100 μM) For example, 10-16h), and then measuring TMA production at each point (e.g., cell lysate and / or isolated enzyme is additionally or alternatively used), One or more dose response curves can be obtained for each compound (eg, as described in Tables 1-8; described herein, etc.). In certain embodiments, typical concentrations used for compounds to inhibit TMA production in intact cell culture are on the order of ˜1 mM. In certain examples, the compound reduced TMA production by ~ 50% at each test point.

In certain instances, experiments employing the techniques described above are performed in E. coli lysate expressing the CutC / CutD or CntA / CntB enzymes from the above-mentioned Proteobacteria and / or Firmicutes bacterial species. Can be

In certain instances, the ability to inhibit TMA degrading enzyme (CutC / CntA), or IC50, can be assessed for an enzyme lysate (eg, on a scale of ˜30 ug) isolated in the presence of the claimed compound, where the enzyme It can be expressed in model organisms (eg E. coli Top10) and then purified. In certain instances, one or more dose response curves can be generated by testing the compound against an isolated enzyme lysate at increasing concentrations in the range between 1 and 1000 μM. In certain examples, the compound's IC50 value is in the range of ˜10 μM.

3. Other

Any of the variants described herein (eg, embodiments, modifications, examples, specific examples, drawings, etc.) and / or any portion of the variants described herein can additionally or alternatively be combined, aggregated, excluded, used , Run continuously, run in parallel and / or applied in different ways.

Some of the implementations of method 100 and / or system 200 may be implemented and / or implemented, at least in part, as a machine configured to receive a computer-readable medium storing computer-readable instructions. The instructions can be executed by computer-executable components that can be integrated with system 200. The computer-readable medium may be stored on RAM, ROM, flash memory, EEPROM, optical device (CD or DVD), hard drive, floppy drive, or other suitable device. The computer-executable component may be a general or application specific processor, but any suitable dedicated hardware or hardware / firmware combination device may alternatively or additionally execute instructions.

As will be appreciated by those skilled in the art from the foregoing detailed description and drawings and claims, methods 100, systems 200 and / or variations are subject to modifications and modifications to the embodiments without departing from the scope defined in the claims. Changes can be made.

Claims (23)

2-ethyl-1-butanol; (2R) -3,3-dimethyl-1,2-butanediol; (2S) -3,3-dimethyl-1,2-butanediol; (2S) -4-methyl-2-pentanol; (2S) -3-methyl-2-butanol; (2R) -4-methyl-2-pentanol; (2R) -3-methyl-2-butanol; (2S) -2-pentanol; (2S) -2-methyl-1,4-butanediol; 2-methyl-2,4-butanediol; Trimethylolpropane; 3- (4-methoxyphenyl) propanal; 1- (3-pyridinyl) -2-propanamine; 2-[(2R) -2-butanyl] phenol; 4-propylbenzoic acid; (2S) -1- (benzyloxy) -2-propanol; Methyl 3- (4-hydroxyphenyl) propanoate; α-methylphenylalanine; 2,2-dimethyl-1-phenyl-1-propanol; Methyl (2R) -hydroxy (phenyl) acetate; (2S) -2-phenylpyrrolidinium; 4-methyl-3-phenyl-1,2-oxazole-5-amine; 4,4'-biphenyldiamine;4'-methyl-2-biphenylcarbonitrile;4-biphenylol; 2- [3- (4-methylphenyl) -1,2-oxazol-5-yl] ethanol; 4-biphenylcarboxamide; 4-ethynylbiphenyl; 5- (4-methylphenyl) -1H-1,2,4-triazole-3-amine; 5- (4-methylphenyl) -1H-pyrazol-3-amine; 4-hydroxycatechol; 3-phenyl-1H-pyrazole-5-carbohydrazide; 4-methyl-1,3-benzenediol; N- (2-hydroxyethyl) -1,3-propanediaminium; 3-methoxy-3-methylbutanol; 4-pyridinylmethaneaminium; N-methyl-3-pyridinamine; 2-methoxypyridine; 5-methyl-3-pyridinamine; 1- (4-methyl-3-pyridinyl) methanamine; Mesitylene; (E) -benzaldoxime '(3R) -2,2,4-trimethyl-1,3-pentanediol; (1R, 4R) -2-azabicyclo [2.2.1] hept-2-ylacetic acid; 3-acetylphenol; 3-hydroxybenzoic acid; 1H-indole-7-ylmethanol; 3-vinyl aniline; (3s, 5s, 7s) -1-isocyanatoadamantine (isocyanatoadamantane); (1R, 2S, 5R) -2-hydroxy-2,6,6-trimethylbicyclo [3.1.1] heptan-3-one; (-)-β-pinene; 2H-isoindole-1,3-diamine; (3s, 5s, 7s) -1-adamantanol; (3-aminobicyclo [2.2.1] hep-2-yl) methanol; 3- (hydrazinomethyl) phenol; (1S, 2R) -2-carbamoylcyclohexaneaminium; (1S, 4R) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; (1R, 4S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; Methyl 4-methyl-4-piperidinecarboxylate; Methyl heptanoate; 3-methylpyridazine; 4,5-dimethyl-1,2-oxazol-3-amine; 2- (2-hydroxyethoxy) phenol; 2-hydroxy-N- (3-pyridinylmethyl) ethanaminium; 3-phenyl-1-propanol; (2R) -6-methyl-2-heptanol; 2-phenoxyacetohydrazide; N-hydroxyoctanamide; Cyclobutanecarbohydrazide; Phenylhydrazine; (1S, 4R) -2-azabicyclo [2.2.1] hep-5-en-3-one; Salicylamide; Adamantane; 3-azabicyclo [3.3.1] nonane; N-hydroxy-2-methylbenzenecarboximideamide; (-)-Campen; (1S, 2S, 4S) -bicyclo [2.2.1] hept-5-en-2-ylmethanol; Dicyclopentadiene; (8-anti) (anti) -3-azabicyclo [3.2.1] octane-8-ol; (1R, 2S, 6R, 7S) -tricyclo [5.2.1.02,6] deca-3,8-diene; Pharmaceutically acceptable form thereof; And a therapeutically effective amount of a compound comprising at least one of salts thereof, a cutline (choline trimethylamine-lyase) enzyme of a microorganism from at least one of Firmicutes (moon) and Proteobacteria (moon) For inhibition, trimethylamine (TMA), trimethylamine N-, comprising administering to a patient having a condition associated with at least one of trimethylamine (TMA), trimethylamine N-oxide (TMAO), and derivatives thereof. A method of treating a patient having a condition associated with at least one of oxide (TMAO), and derivatives thereof.

The method of claim 1, wherein the condition comprises at least one of a cardiovascular condition and a renal condition associated with at least one of TMA, TMAO and derivatives thereof, and the step of administering to a patient having the condition comprises: Firmicutes ( For the inhibition of choline trimethylamine-lyase (CutC) enzymes of microorganisms from at least one of Q) and Proteobacteria (Q), a therapeutically effective amount of the compound is administered to a patient having at least one of cardiovascular and renal conditions. A method comprising administering.
The method of claim 2, wherein the condition comprises a cardiovascular condition comprising atherosclerosis condition associated with at least one of TMA, TMAO and derivatives thereof, and the step of administering to a patient having the condition is Firmicutes . Administering a therapeutically effective amount of the compound to a patient with atherosclerosis condition for inhibition of the choline trimethylamine-lyase (CutC) enzyme of microorganisms from at least one of (Moon) and Proteobacteria (Moon) Including, method.
3. The method of claim 2, wherein the condition comprises a cardiovascular disease comprising at least one of an augmented platelet aggregation condition and a thrombus formation condition associated with at least one of TMA, TMAO and derivatives thereof, and administering to the patient having the condition. Is, for the inhibition of microbial CutC (choline trimethylamine-lyase) enzymes from at least one of Firmicutes (moon) and Proteobacteria (moon), platelet enhanced therapeutically effective amount of the compound A method comprising administering to a patient having at least one of an agglutination condition and a thrombus formation condition.
According to claim 1, The step of administering to the patient having the condition is 2-ethyl-1-butanol; (2R) -3,3-dimethyl-1,2-butanediol; (2S) -3,3-dimethyl-1,2-butanediol; (2S) -4-methyl-2-pentanol; (2S) -3-methyl-2-butanol; (2R) -4-methyl-2-pentanol; (2R) -3-methyl-2-butanol; (2S) -2-pentanol; (2S) -2-methyl-1,4-butanediol; 2-methyl-2,4-butanediol; Trimethylolpropane; Pharmaceutically acceptable form thereof; And administering a therapeutically effective amount of a compound comprising a 3,3-dimethyl-1-butanol (DMB) analog comprising at least one of its salts to a patient having said condition.
The method of claim 1, wherein the microorganism comprises microorganisms from Firmicutes (moon), and the step of administering to a patient having the condition is CutC enzymes of microorganisms from Firmicutes (moon). Administering a therapeutically effective amount of the compound to a patient with the condition for inhibition, the compound comprising at least one of the following: method: 3- (4-methoxyphenyl) propanal; 1- (3-pyridinyl) -2-propanamine; 2-[(2R) -2-butanyl] phenol; 4-propylbenzoic acid; (2S) -1- (benzyloxy) -2-propanol; Methyl 3- (4-hydroxyphenyl) propanoate; α-methylphenylalanine; 2,2-dimethyl-1-phenyl-1-propanol; Methyl (2R) -hydroxy (phenyl) acetate; (2S) -2-phenylpyrrolidinium; 4-methyl-3-phenyl-1,2-oxazole-5-amine; 4,4'-biphenyldiamine;4'-methyl-2-biphenylcarbonitrile;4-biphenylol; 2- [3- (4-methylphenyl) -1,2-oxazol-5-yl] ethanol; 4-biphenylcarboxamide; 4-ethynylbiphenyl; 5- (4-methylphenyl) -1H-1,2,4-triazole-3-amine; 5- (4-methylphenyl) -1H-pyrazol-3-amine; 4-hydroxycatechol; 3-phenyl-1H-pyrazole-5-carbohydrazide; 4-methyl-1,3-benzenediol; Pharmaceutically acceptable forms thereof, and salts thereof.
The method of claim 1, wherein the microorganism comprises microorganisms from Proteobacteria (moon), and the step of administering to a patient having the condition is Proteobacteria (moon) to the patient having the condition. A method comprising: administering a therapeutically effective amount of said compound to inhibit the CutC enzyme of a microorganism from, wherein said compound comprises at least one of the following: N- (2-hydroxyethyl) -1,3- Propanedianium; 3-methoxy-3-methylbutanol; 4-pyridinylmethaneaminium; N-methyl-3-pyridinamine; 2-methoxypyridine; 5-methyl-3-pyridinamine; 1- (4-methyl-3-pyridinyl) methanamine; Mesitylene; (E) -benzaldoxime '(3R) -2,2,4-trimethyl-1,3-pentanediol; (1R, 4R) -2-azabicyclo [2.2.1] hept-2-ylacetic acid; 3-acetylphenol; 3-hydroxybenzoic acid; 1H-indole-7-ylmethanol; 3-vinyl aniline; (3s, 5s, 7s) -1-isocyanatoadamantane; (1R, 2S, 5R) -2-hydroxy-2,6,6-trimethylbicyclo [3.1.1] heptan-3-one; (-)-β-pinene; 2H-isoindole-1,3-diamine; (3s, 5s, 7s) -1-adamantanol; (3-aminobicyclo [2.2.1] hep-2-yl) methanol; 3- (hydrazinomethyl) phenol; (1S, 2R) -2-carbamoylcyclohexaneaminium; (1S, 4R) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; (1R, 4S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; Pharmaceutically acceptable forms thereof, and salts thereof.
The method of claim 1, wherein the microorganism comprises microorganisms from Firmicutes (moon) and Proteobacteria (moon), and the step of administering to a patient having the condition is Firmicutes. ) (Moon) and Proteobacteria (Moon), comprising the step of administering a therapeutically effective amount of the compound to a patient having the condition for inhibition of the CutC enzyme of microorganisms, wherein the compound is at least one of the following The method comprising: methyl 4-methyl-4-piperidinecarboxylate; Methyl heptanoate; 3-methylpyridazine; 4,5-dimethyl-1,2-oxazol-3-amine; 2- (2-hydroxyethoxy) phenol; 2-hydroxy-N- (3-pyridinylmethyl) ethanaminium; 3-phenyl-1-propanol; (2R) -6-methyl-2-heptanol; 2-phenoxyacetohydrazide; N-hydroxyoctanamide; Cyclobutanecarbohydrazide; Phenylhydrazine; (1S, 4R) -2-azabicyclo [2.2.1] hep-5-en-3-one; Salicylamide; Adamantane; 3-azabicyclo [3.3.1] nonane; N-hydroxy-2-methylbenzenecarboximideamide; (-)-Campen; (1S, 2S, 4S) -bicyclo [2.2.1] hept-5-en-2-ylmethanol; Dicyclopentadiene; (8-anti) -3-azabicyclo [3.2.1] octane-8-ol; (1R, 2S, 6R, 7S) -tricyclo [5.2.1.02,6] deca-3,8-diene; Pharmaceutically acceptable forms thereof, and salts thereof.
N-methylglutamic acid; 4- (1-pyrrolidinyl) butanoic acid; 4-methyl-4-piperidinecarboxylic acid; Isonifecotic acid; N-propylbenzene; N-ethyl-2-pyridinamine; (4R) -4-amino-1-propyl-2-pyrrolidinone; 2,5-diaminotoluene; Ethyl phenyl ether; Phenyl cyanate; 1- (2-cyclopenten-1-yl) acetone; 2-amino-3-methylpyridinium; E-pyridine-3-aldoxime; N-cyclohexyl formamide; 2-methyl-2-hexenic acid (hexenoic acid); 4-heptanaminium; 3,4-anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid; 2,2 '-[(2-hydroxyethyl) imino] diacetic acid; 1H-tetrazol-5-ylacetic acid; Diacetylacetone; (2S) -2-acetoxy propanoic acid; 4,4'-biphthalic anhydride; Bis (1H-benzotriazol-1-yl) methanone; 2-anthraquinone sulfonic acid; 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzonitrile .; 2-phenylquinazolin-4-ol; 4-amino-2- (1,3-benzothiazol-2-yl) phenol; 4-phenyl-1 (2H) -phthalazinone; 5- (1,3-benzodioxol-5-yl) -2-methyl-3-furo acid; (5R) -5- (2-naphthyl) dihydro-2 (3H) -furanone; 3- [5- (3-methylphenyl) -1,3,4-oxadiazol-2-yl] propanoic acid; 9-ethynylphenanthrene; PHA-767491; 3-amino-2-methylphenol; 5- (4-methylphenyl) -2-furo acid; 8-methyl-4H-thieno [3,2-c] chromen-2-carboxylic acid; Resorcinol monobenzoate; 3-methoxy-4-biphenylcarbaldehyde; (7-amino-4-methyl-2-oxo-2H-chromen-3-yl) acetic acid; 2,3-dihydro-1H-inden-5-yl (oxo) acetic acid; 3- (2-pyridyl) aniline; 4- (3-methyl-1H-1,2,4-triazol-5-yl) aniline; Benzidine; (DL) -3-O-methyldopa; Methyl (2E) -3- (2-amino-5-methyl-3-pyridinyl) acrylate; (5-methylfuro [2,3-b] pyridin-2-yl) methanol; (2R) -2,3-dihydro-1,4-benzodioxin-2-ylmethaneaminium; R-phenylethyl propionate; i-propyl benzoate; 4-acetotoluide; (1S) -1- (2,5-dimethylphenyl) ethanaminium; (1R) -2-methyl-2,5-cyclohexadiene-1-carboxylic acid; (2,2-dimethoxyethyl) benzene; Lie of a microorganism from at least one of Firmicutes (Moon) and Proteobacteria (Moon) to a therapeutically effective amount of a compound comprising at least one of its pharmaceutically acceptable forms, and salts thereof. Administering to a patient with a condition associated with at least one of trimethylamine (TMA), trimethylamine N-oxide (TMAO), and derivatives thereof for inhibition of Rieske-type oxigenase (CntA) enzymes A method of treating a patient having a condition associated with at least one of trimethylamine (TMA), trimethylamine N-oxide (TMAO), and derivatives thereof, comprising:
The method of claim 9, wherein the condition comprises at least one of a cardiovascular condition and a renal condition associated with at least one of TMA, TMAO and derivatives thereof, and administering to a patient having the condition comprises administering a therapeutically effective amount of the compound. Administering to a patient having at least one of cardiovascular and renal conditions for the inhibition of CntA enzymes of microorganisms from at least one of Firmicutes (moon) and Proteobacteria (moon), Way.
The method of claim 10, wherein the condition comprises a cardiovascular condition comprising atherosclerosis condition associated with at least one of TMA, TMAO and derivatives thereof, and the step of administering to the patient having the condition comprises: Administering a therapeutically effective amount to a patient with atherosclerosis condition for inhibiting CntA enzymes of microorganisms from at least one of Firmicutes (moon) and Proteobacteria (moon), Way.
The method of claim 10, wherein the condition comprises a cardiovascular disease comprising at least one of an augmented platelet aggregation condition and a thrombus formation condition associated with at least one of TMA, TMAO and derivatives thereof, and administering to a patient having the condition. Is, during the increased platelet aggregation condition and thrombus formation condition for inhibiting CntA enzyme of microorganisms from at least one of Firmicutes (moon) and Proteobacteria (moon) And administering to a patient having at least one.
The method of claim 9, wherein the condition comprises at least one of a metabolic-related condition and a nutrition-related condition associated with at least one of TMA, TMAO and derivatives thereof, and administering to a patient having the condition comprises: Patients with at least one of a metabolic-related condition and a nutrition-related condition for inhibiting CntA enzymes of a microorganism from a therapeutically effective amount of at least one of Firmicutes (moon) and Proteobacteria (moon) Method comprising the step of administering to.
14. The method of claim 13, wherein at least one of the metabolic-related condition and nutrition-related condition comprises at least one of a weight-related condition and a hyperglycemic-related condition associated with at least one of TMA, TMAO and derivatives thereof. The step of administering to a patient having a weight-related condition for inhibiting CntA enzymes of microorganisms from at least one of Firmicutes (Moon) and Proteobacteria (Moon) is administered in a therapeutically effective amount of the compound. And administering to a patient having at least one of hyperglycemic-related conditions.
14. The method of claim 13, wherein the condition comprises a trimethylamineuria (TMAU) condition associated with at least one of TMA, TMAO and derivatives thereof, and administering to a patient having the condition comprises: A method comprising administering to a patient with a TMAU condition for inhibition of CntA enzymes of microorganisms from at least one of Firmicutes (moon) and Proteobacteria (moon).
10. The method of claim 9, wherein the step of administering to a patient with a condition is N-methylglutamic acid; 4- (1-pyrrolidinyl) butanoic acid; 4-methyl-4-piperidinecarboxylic acid; Isonifecotic acid; Pharmaceutically acceptable form thereof; And administering to a patient having said condition a therapeutically effective amount of a compound comprising an L-cartinine analog comprising at least one of its salts.
The method of claim 9, wherein the microorganism comprises microorganisms from Firmicutes (moon), and the step of administering to a patient having the condition is CntA enzyme of microorganisms from Firmicutes (moon). Administering a therapeutically effective amount of the compound to a patient with the condition for inhibition, the compound comprising at least one of the following: method: N-propylbenzene; N-ethyl-2-pyridinamine; (4R) -4-amino-1-propyl-2-pyrrolidinone; 2,5-diaminotoluene; Ethyl phenyl ether; Phenyl cyanate; 1- (2-cyclopenten-1-yl) acetone; 2-amino-3-methylpyridinium; E-pyridine-3-aldoxime; N-cyclohexyl formamide; 2-methyl-2-hexenic acid; 4-heptanaminium; Pharmaceutically acceptable forms thereof, and salts thereof.
The method of claim 9, wherein the microorganism comprises a microorganism from Proteobacteria ( Proteobacteria ) (moon), and the step of administering to a patient having the condition is a CntA enzyme of a microorganism from Proteobacteria (moon) Administering a therapeutically effective amount of said compound to a patient with said condition for inhibition, said compound comprising at least one of the following: 3,4-anhydro-3-carboxy-2-de Oxy-L-threo-pentaric acid; 2,2 '-[(2-hydroxyethyl) imino] diacetic acid; 1H-tetrazol-5-ylacetic acid; Diacetylacetone; (2S) -2-acetoxypropanoic acid; Pharmaceutically acceptable form thereof; And salts thereof.
The method of claim 9, wherein the microorganism comprises microorganisms from Firmicutes (moon) and Proteobacteria (moon), and the step of administering to a patient having the condition is Firmicutes. ) (Moon) and Proteobacteria (Moon) comprising administering a therapeutically effective amount of the compound to a patient having the condition for inhibition of CntA enzymes of microorganisms, wherein the compound is at least one of the following: Method comprising: 4,4'-biphthalic anhydride; Bis (1H-benzotriazol-1-yl) methanone; 2-anthraquinone sulfonic acid; 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzonitrile .; 2-phenylquinazolin-4-ol; 4-amino-2- (1,3-benzothiazol-2-yl) phenol; 4-phenyl-1 (2H) -phthalazinone; 5- (1,3-benzodioxol-5-yl) -2-methyl-3-furo acid; (5R) -5- (2-naphthyl) dihydro-2 (3H) -furanone; 3- [5- (3-methylphenyl) -1,3,4-oxadiazol-2-yl] propanoic acid; 9-ethynylphenanthrene; PHA-767491; 3-amino-2-methylphenol; 5- (4-methylphenyl) -2-furo acid; 8-methyl-4H-thieno [3,2-c] chromen-2-carboxylic acid; Resorcinol monobenzoate; 3-methoxy-4-biphenylcarbaldehyde; (7-amino-4-methyl-2-oxo-2H-chromen-3-yl) acetic acid; 2,3-dihydro-1H-inden-5-yl (oxo) acetic acid; 3- (2-pyridyl) aniline; 4- (3-methyl-1H-1,2,4-triazol-5-yl) aniline; Benzidine; (DL) -3-O-methyldopa; Methyl (2E) -3- (2-amino-5-methyl-3-pyridinyl) acrylate; (5-methylfuro [2,3-b] pyridin-2-yl) methanol; (2R) -2,3-dihydro-1,4-benzodioxin-2-ylmethaneaminium; R-phenylethyl propionate; i-propyl benzoate; 4-acetotoluide; (1S) -1- (2,5-dimethylphenyl) ethanaminium; (1R) -2-methyl-2,5-cyclohexadiene-1-carboxylic acid; (2,2-dimethoxyethyl) benzene; Pharmaceutically acceptable forms thereof, and salts thereof.
Determining a representative sequence of an enzyme associated with at least one of TMA, TMAO and derivatives thereof, wherein the representative sequence represents a sequence set of enzymes for at least one taxonomic group from a microbial taxa set;
Generating a protein structural model of the enzyme based on the representative sequence of the enzyme;
Determining a control binding parameter for an enzyme based on a protein structure model and a control docking simulation using a control molecule;
Determining a set of compound binding parameters for an enzyme based on a set of compound docking simulations using a protein structure model and a compound library; And
Identifying at least one compound from the compound library to treat a patient with a condition associated with at least one of TMA, TMAO and derivatives thereof, based on a comparison between a set of control binding parameters and a set of compound binding parameters. ;
A method of identifying at least one compound for treating a patient having a condition associated with at least one of trimethylamine (TMA), trimethylamine N-oxide (TMAO), and derivatives thereof comprising a.
The method of claim 20, wherein the enzyme comprises at least one of choline trimethylamine-degrading enzyme (Choline trimethylamine-lyase, CutC) enzyme and Rieske-type oxygenase (CntA) enzyme, the at least The method of one taxa comprising at least one of Firmicutes (moon) and Proteobacteria (moon).
22. The method of claim 21, wherein the at least one compound comprises at least one of: 2-ethyl-1-butanol; (2R) -3,3-dimethyl-1,2-butanediol; (2S) -3,3-dimethyl-1,2-butanediol; (2S) -4-methyl-2-pentanol; (2S) -3-methyl-2-butanol; (2R) -4-methyl-2-pentanol; (2R) -3-methyl-2-butanol; (2S) -2-pentanol; (2S) -2-methyl-1,4-butanediol; 2-methyl-2,4-butanediol; Trimethylolpropane; 3- (4-methoxyphenyl) propanal; 1- (3-pyridinyl) -2-propanamine; 2-[(2R) -2-butanyl] phenol; 4-propylbenzoic acid; (2S) -1- (benzyloxy) -2-propanol; Methyl 3- (4-hydroxyphenyl) propanoate; α-methylphenylalanine; 2,2-dimethyl-1-phenyl-1-propanol; Methyl (2R) -hydroxy (phenyl) acetate; (2S) -2-phenylpyrrolidinium; 4-methyl-3-phenyl-1,2-oxazole-5-amine; 4,4'-biphenyldiamine;4'-methyl-2-biphenylcarbonitrile;4-biphenylol; 2- [3- (4-methylphenyl) -1,2-oxazol-5-yl] ethanol; 4-biphenylcarboxamide; 4-ethynylbiphenyl; 5- (4-methylphenyl) -1H-1,2,4-triazole-3-amine; 5- (4-methylphenyl) -1H-pyrazol-3-amine; 4-hydroxycatechol; 3-phenyl-1H-pyrazole-5-carbohydrazide; 4-methyl-1,3-benzenediol; N- (2-hydroxyethyl) -1,3-propanediaminium; 3-methoxy-3-methylbutanol; 4-pyridinylmethaneaminium; N-methyl-3-pyridinamine; 2-methoxypyridine; 5-methyl-3-pyridinamine; 1- (4-methyl-3-pyridinyl) methanamine; Mesitylene; (E) -benzaldoxime '(3R) -2,2,4-trimethyl-1,3-pentanediol; (1R, 4R) -2-azabicyclo [2.2.1] hept-2-ylacetic acid; 3-acetylphenol; 3-hydroxybenzoic acid; 1H-indole-7-ylmethanol; 3-vinyl aniline; (3s, 5s, 7s) -1-isocyanatoadamantine (isocyanatoadamantane); (1R, 2S, 5R) -2-hydroxy-2,6,6-trimethylbicyclo [3.1.1] heptan-3-one; (-)-β-pinene; 2H-isoindole-1,3-diamine; (3s, 5s, 7s) -1-adamantanol; (3-aminobicyclo [2.2.1] hep-2-yl) methanol; 3- (hydrazinomethyl) phenol; (1S, 2R) -2-carbamoylcyclohexaneaminium; (1S, 4R) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; (1R, 4S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-one; Methyl 4-methyl-4-piperidinecarboxylate; Methyl heptanoate; 3-methylpyridazine; 4,5-dimethyl-1,2-oxazol-3-amine; 2- (2-hydroxyethoxy) phenol; 2-hydroxy-N- (3-pyridinylmethyl) ethanaminium; 3-phenyl-1-propanol; (2R) -6-methyl-2-heptanol; 2-phenoxyacetohydrazide; N-hydroxyoctanamide; Cyclobutanecarbohydrazide; Phenylhydrazine; (1S, 4R) -2-azabicyclo [2.2.1] hep-5-en-3-one; Salicylamide; Adamantane; 3-azabicyclo [3.3.1] nonane; N-hydroxy-2-methylbenzenecarboximideamide; (-)-Campen; (1S, 2S, 4S) -bicyclo [2.2.1] hept-5-en-2-ylmethanol; Dicyclopentadiene; (8-anti) -3-azabicyclo [3.2.1] octane-8-ol; (1R, 2S, 6R, 7S) -tricyclo [5.2.1.02,6] deca-3,8-diene; N-methylglutamic acid; 4- (1-pyrrolidinyl) butanoic acid; 4-methyl-4-piperidinecarboxylic acid; Isonifecotic acid; N-propylbenzene; N-ethyl-2-pyridinamine; (4R) -4-amino-1-propyl-2-pyrrolidinone; 2,5-diaminotoluene; Ethyl phenyl ether; Phenyl cyanate; 1- (2-cyclopenten-1-yl) acetone; 2-amino-3-methylpyridinium; E-pyridine-3-aldoxime; N-cyclohexyl formamide; 2-methyl-2-hexenic acid; 4-heptanaminium; 3,4-anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid; 2,2 '-[(2-hydroxyethyl) imino] diacetic acid; 1H-tetrazol-5-ylacetic acid; Diacetylacetone; (2S) -2-acetoxypropanoic acid; 4,4'-biphthalic anhydride; Bis (1H-benzotriazol-1-yl) methanone; 2-anthraquinone sulfonic acid; 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzonitrile .; 2-phenylquinazolin-4-ol; 4-amino-2- (1,3-benzothiazol-2-yl) phenol; 4-phenyl-1 (2H) -phthalazinone; 5- (1,3-benzodioxol-5-yl) -2-methyl-3-furo acid; (5R) -5- (2-naphthyl) dihydro-2 (3H) -furanone; 3- [5- (3-methylphenyl) -1,3,4-oxadiazol-2-yl] propanoic acid; 9-ethynylphenanthrene; PHA-767491; 3-amino-2-methylphenol; 5- (4-methylphenyl) -2-furo acid; 8-methyl-4H-thieno [3,2-c] chromen-2-carboxylic acid; Resorcinol monobenzoate; 3-methoxy-4-biphenylcarbaldehyde; (7-amino-4-methyl-2-oxo-2H-chromen-3-yl) acetic acid; 2,3-dihydro-1H-inden-5-yl (oxo) acetic acid; 3- (2-pyridyl) aniline; 4- (3-methyl-1H-1,2,4-triazol-5-yl) aniline; Benzidine; (DL) -3-O-methyldopa; Methyl (2E) -3- (2-amino-5-methyl-3-pyridinyl) acrylate; (5-methylfuro [2,3-b] pyridin-2-yl) methanol; (2R) -2,3-dihydro-1,4-benzodioxin-2-ylmethaneaminium; R-phenylethyl propionate; i-propyl benzoate; 4-acetotoluide; (1S) -1- (2,5-dimethylphenyl) ethanaminium; (1R) -2-methyl-2,5-cyclohexadiene-1-carboxylic acid; (2,2-dimethoxyethyl) benzene; Pharmaceutically acceptable forms thereof, and salts thereof.
23. The method of claim 22, wherein the condition comprises at least one of a cardiovascular condition, a renal condition, a metabolic-related condition and a nutrition-related condition.

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